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Objective To observe change of proliferation, migration and invasion abilities of pancreatic cancer cells with over-/down-expression of circSTON2, and to preliminarily investigate the biological function of circSTON2 in pancreatic cancer. Methods Human pancreatic cancer cell line PANC-1 was in vitro cultured. CircSTON2 over-expression group, circSTON2 down-expression group, and control group were established. Plasmid transfection and siRNA interference were used to transfect the circSTON2 overexpression plasmid and circSTON2-siRNA interference plasmid and blank control plasmid into the above groups. At 24, 36 and 48 hours of culture, CCK-8 assay was used to detect cell proliferation and Transwell assay was used to detect cell migration and invasion. Results At 24, 36 and 48 hours of culture, cell proliferation ability was as follows: circSTON2 over-expression group > control group > circSTON2 down-expression group (all P<0. 05); the number of migration cells and the number of invasion cells were as follows: circSTON2 over-expression group > control group > circSTON2 down-expression group (all P<0. 05）. Conclusions The over-expression of circSTON2 promotes proliferation, migration, and invasion of pancreatic cancer cells. However, the effect of down-expression of circSTON2 is the opposite. [ABSTRACT FROM AUTHOR]

Statistically significant violations of the Clauser–Horne–Shimony–Holt (CHSH) inequality are the "gold standard" test for quantum entanglement between spatially separated systems. Here, we report an experimental design that implements a CHSH test between bioelectric state variables for a human subject and bioelectric and/or biochemical state variables for cultured human cells in vitro. While we were unable to obtain evidence for entanglement with this design, observing only classical correlation, we report lessons learned and suggest possible avenues for future studies. [ABSTRACT FROM AUTHOR]

Statistically significant violations of the Clauser–Horne–Shimony–Holt (CHSH) inequality are the “gold standard” test for quantum entanglement between spatially separated systems. Here, we report an experimental design that implements a CHSH test between bioelectric state variables for a human subject and bioelectric and/or biochemical state variables for cultured human cells in vitro. While we were unable to obtain evidence for entanglement with this design, observing only classical correlation, we report lessons learned and suggest possible avenues for future studies.

Individuals diagnosed with cancer often turn to the use of herbal remedies with the intention of treating and ameliorating the condition, impeding the progression of metastasis, enhancing immune function, mitigating stress, and inducing relaxation. Recently, medicinal plants were combined with conventional chemotherapy to decrease the side effects and increase the effectiveness of chemotherapy. This study showed the effectiveness of gemcitabine (Gem) was significantly increased after being used together with ethyl acetate extract obtained from Vernonia amygdalina (Eav) leaves. The combination doses of Eav and Gem were determined based on cytotoxic activity using the MTT assay method. The anticancer effect of this combination was identified by several parameters including the apoptosis effect, anti-migration, and anti-invasion activities of PANC-1 cells. Furthermore, this effect was explained via protein expression evaluation using immunohistochemical and flow cytometry. The Eav has a better Inhibitory Concentration 50 (IC50) than Gem of 21.19 ± 0.64 µg/mL and 164.78 ± 1.40 µg/mL. The combination of Eav and Gem at IC50 (1:1) has the strongest activity than Eav and Gem alone at 500.00 µg/mL. The anti-cancer effect of this combination showed significantly increased levels of apoptosis, particularly in the early phase of 17.46 ± 0.35 % (p

Pancreatic cancer is a highly lethal and malignant tumor with high occurrence worldwide. Natural products such as essential oils with a lack of side effects may benefit pancreatic cancer supplementary therapy. Essential oil of BS was prepared by distillation of the gum resin and also has been shown to have anti-cancer and antioxidant activities. The present study aimed to determine the anti-cancer, antioxidant and anti-inflammatory activities in PANC-1 cells. Chemical Functional Moieties of Boswellia sacra essential oil were determined by Fourier transform infrared (FTIR) spectroscopy. The essential oil was simultaneously analyzed by GC/MS and GC-FID. Cell viability was determined by MTT assay. Anti-cancer activity of BS essential oil was investigated by immunocytochemistry using antibodies against STAT-3, IHH, β-catenin, CD133, and Ki-67. The antioxidant activity of BS essential oil was tested by DPPH method. 41 compounds were identified in the essential oil. The IC50 value of BS essential oil was found as 130 μg/mL in PANC-1 cells. Ki-67 immunoreactivity significantly decreased in BS essential oil-treated PANC-1 cells. STAT-3 and β-catenin immunoreactivities significantly increased in BS essential oil-treated PANC-1 cells. Also, BS essential oil showed antioxidant and anti-inflammatory activities. We conclude that BS essential oil may suppress proliferation via the β-catenin activation pathway in PANC-1 cells. [ABSTRACT FROM AUTHOR]

Iron oxide nanoparticles are one of the most promising tools for theranostic applications of pancreatic cancer due to their unique physicochemical and magnetic properties making them suitable for both diagnosis and therapy. Thus, our study aimed to characterize the properties of dextran-coated iron oxide nanoparticles (DIO-NPs) of maghemite (γ-Fe2O3) type synthesized by co-precipitation and to investigate their effects (low-dose versus high-dose) on pancreatic cancer cells focusing on NP cellular uptake, MR contrast, and toxicological profile. This paper also addressed the modulation of heat shock proteins (HSPs) and p53 protein expression as well as the potential of DIO-NPs for theranostic purposes. DIO-NPs were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering analyses (DLS), and zeta potential. Pancreatic cancer cells (PANC-1 cell line) were exposed to different doses of dextran-coated ɣ-Fe2O3 NPs (14, 28, 42, 56 μg/mL) for up to 72 h. The results revealed that DIO-NPs with a hydrodynamic diameter of 16.3 nm produce a significant negative contrast using a 7 T MRI scanner correlated with dose-dependent cellular iron uptake and toxicity levels. We showed that DIO-NPs are biocompatible up to a concentration of 28 μg/mL (low-dose), while exposure to a concentration of 56 μg/mL (high-dose) caused a reduction in PANC-1 cell viability to 50% after 72 h by inducing reactive oxygen species (ROS) production, reduced glutathione (GSH) depletion, lipid peroxidation, enhancement of caspase-1 activity, and LDH release. An alteration in Hsp70 and Hsp90 protein expression was also observed. At low doses, these findings provide evidence that DIO-NPs could act as safe platforms in drug delivery, as well as antitumoral and imaging agents for theranostic uses in pancreatic cancer. [ABSTRACT FROM AUTHOR]

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Type 1 diabetes mellitus is an autoimmune disorder leading to loss of beta cells. There is a dire need to inhibit apoptosis and induce regeneration of new beta cells. There are plants in the Indian medicine system having the potential for rejuvenation. In the present study, we have attempted to evaluate the capacity of aqueous extract of Tinospora cordifolia to regenerate beta cells from PANC-1 ductal cells. After differentiation, the characterization of β-cell phenotype was carried out using dithizone and Gomori's staining and further confirmed by mRNA expression study of insulin, Pdx-1, and carbonic anhydrase-9. Insulin production was estimated with ELISA. Aqueous extract of Tinospora cordifolia at 15 μg/ml concentration can effectively induce differentiation of PANC-1 cells into beta cells. The morphological observations showed brownish-colored dithizone and purple-colored Gomori's staining. The β-cells demonstrated significant mRNA expression of insulin and Pdx-1 and downregulation of carbonic anhydrase-9. The functionality of beta cells was demonstrated by 1.5-fold increase in insulin secretion in response to high glucose. Tinospora cordifolia has potential to differentiate PANC-1 ductal cells into functional beta cells and can be a lead towards non-invasive treatment of type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Mycoplasma contamination is a common problem in cell culture and can alter cellular functions. Since cell metabolism is either directly or indirectly involved in every aspect of cell function, it is important to detect changes to the cellular metabolome after mycoplasma infection. In this study, liquid chromatography mass spectrometry (LC/MS)-based metabolomics was used to investigate the effect of mycoplasma contamination on the cellular metabolism of human pancreatic carcinoma cells (PANC-1). Multivariate analysis demonstrated that mycoplasma contamination induced significant metabolic changes in PANC-1 cells. Twenty-three metabolites were identified and found to be involved in arginine and purine metabolism and energy supply. This study demonstrates that mycoplasma contamination significantly alters cellular metabolite levels, confirming the compelling need for routine checking of cell cultures for mycoplasma contamination, particularly when used for metabolomics studies. Graphical abstract Metabolomics reveals mycoplasma contamination changes the metabolome of PANC-1 cells.

Introduction. Suppressing the phenotype of cancer stem cells (CSCs) is a promising treatment strategy for cancer. P38 mitogen-activated protein kinases (MAPK, p38) play an important role in the occurrence, development, and stemness maintenance of tumors. The aim of the current study was to investigate the effect of p38 on the stemness maintenance of CSCs in pancreatic cancer cell line PANC-1. Material and methods. PANC-1 human pancreatic cancer cells were treated with 5-fluorouracil (5-FU) at 0.5 IC50, IC50, and 2 IC50 for 24 h. PANC-1 cells were treated for 24 h with 5-FU at 0.5IC50, IC50, and 2IC50 with or without VX-702, p38 phosphorylation inhibitor. Cells were resuspended in DMEM supplemented with 20 ng/ml epidermal growth factor, 2% B27, 5 mg/ml insulin, 20 g/ml basic fibroblast growth factor, and 10 µg/ml transferrin. Cells were seeded in ultra-low adhesion 6-well dishes to observe tumor spheroidization. The expression of CDK2, cyclin B1, cyclin D1, OCT4, SOX2, Nanog, and p38 was measured by Western blot. The mRNA expression of p38, OCT4, Nanog, and SOX2 was measured by RT-PCR. Flow cytometry was performed to evaluate the cell cycle, apoptosis, and proportion of CD44+CD133+ PANC-1 cells. Results. 5-FU decreased cell viability and increased apoptosis. 5-FU suppressed the stemness maintenance of CSCs in PANC-1 cells, as demonstrated by the inhibition of tumorsphere formation, the decrease in CD44+CD133+ cells’ fraction, and downregulation of OCT4, Nanog, and SOX2 expression. In addition, 5-FU inhibited the phosphorylation of p38 in PANC-1 cells. The phosphorylation of p38 was subsequently suppressed by VX-702, p38 mitogen-activated protein kinase inhibitor, which exhibited similar effects as those of 5-FU treatment. The effect of VX-702 on PANC-1 cells was further enhanced by 5-FU treatment. Thus, p38 inhibitor decreased the viability and increased the apoptosis of PANC-1 cells. P38 inhibitor suppressed the stemness maintenance of CSCs in PANC-1 cells, as demonstrated by the inhibition of tumorsphere formation, the decrease in CD44+CD133+ cells, and the downregulation of OCT4, Nanog, and SOX2 expression. Conclusions. These findings indicate that the inhibition of p38 phosphorylation suppresses the stemness maintenance and 5-FU resistance of PANC-1 cells, providing a potential therapeutic target for the prevention and treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Regulated cell death by way of ferroptosis involves iron-dependent accumulation of cellular reactive oxygen species (ROS). Ferroptosis is attracting attention as a potential therapeutic target for cancer treatments without drug resistance. The relationship between irisin, a myokine involved in autophagy and ROS metabolism, and ferroptosis is unclear. In this study, we used erastin-induced ferroptosis in PANC-1 cells to examine potential interactions of irisin with ferroptosis. Using western blots and reverse transcriptase polymerase chain reactions, we found that irisin can further exacerbate erastin-induced upregulation in free iron, lipid ROS levels, and glutathione depletion, relative to cells treated with erastin only. Conversely, removal of irisin limited erastin effects. Furthermore, irisin modulation of ferroptosis was associated with the expression changes in molecules important for ROS metabolism, iron metabolism, and the cysteine/glutamate antiporter system (system Xc−). These study findings suggest that irisin can act as a master factor of ferroptosis, and that potential implications for harnessing irisin-mediated ferroptosis for cancer treatment are warranted.

Iron oxide nanoparticles are one of the most promising tools for theranostic applications of pancreatic cancer due to their unique physicochemical and magnetic properties making them suitable for both diagnosis and therapy. Thus, our study aimed to characterize the properties of dextran-coated iron oxide nanoparticles (DIO-NPs) of maghemite (γ-Fe2O3) type synthesized by co-precipitation and to investigate their effects (low-dose versus high-dose) on pancreatic cancer cells focusing on NP cellular uptake, MR contrast, and toxicological profile. This paper also addressed the modulation of heat shock proteins (HSPs) and p53 protein expression as well as the potential of DIO-NPs for theranostic purposes. DIO-NPs were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering analyses (DLS), and zeta potential. Pancreatic cancer cells (PANC-1 cell line) were exposed to different doses of dextran-coated ɣ-Fe2O3 NPs (14, 28, 42, 56 μg/mL) for up to 72 h. The results revealed that DIO-NPs with a hydrodynamic diameter of 16.3 nm produce a significant negative contrast using a 7 T MRI scanner correlated with dose-dependent cellular iron uptake and toxicity levels. We showed that DIO-NPs are biocompatible up to a concentration of 28 μg/mL (low-dose), while exposure to a concentration of 56 μg/mL (high-dose) caused a reduction in PANC-1 cell viability to 50% after 72 h by inducing reactive oxygen species (ROS) production, reduced glutathione (GSH) depletion, lipid peroxidation, enhancement of caspase-1 activity, and LDH release. An alteration in Hsp70 and Hsp90 protein expression was also observed. At low doses, these findings provide evidence that DIO-NPs could act as safe platforms in drug delivery, as well as antitumoral and imaging agents for theranostic uses in pancreatic cancer.

Development of novel methods is needed for the synthesis of nanoparticles. Attention on such particles has elevated disquiet about the eco-friendly manner of their fabrication methods. In the present study, we equipped and synthesized gold nanoparticles (AuNPs) from Panax notoginseng; investigated as an environmentally friendly and non-toxic substrate. Amalgamation of AuNPs was distinguished by numerous studies such as UV-absorbance and it shows peak values in the range of 520–550 nm. Nanoparticles sizes are confirmed by dynamic light scattering analysis and it shows 100 nm. Moreover, transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDX) confirmed the shape of the Au particles present in the synthesized materials. FTIR analysis studies showed the active molecules positioned in the plane of the synthesized particles. The anticancer potential of AuNPs was evaluated in PANC-1 cells. Additionally, AuNPs efficiently induced cytotoxicity, ROS and apoptosis by intonating intrinsic apoptotic gene expressions in PANC-1 cells. Finally, our study confirmed the synthesis of AuNPs from Panax notoginseng, which showed anticancer effects in an environmentally friendly manner.

Increasing evidence shows that eukaryotic initiation factor subunit (EIF3C) plays a crucial role in development of tumors. However, the underlying roles of EIF3Cin the development of pancreatic cancer (PC) remain unknown. In this study, we examined the expression of EIF3C in PC tissues, their adjacent normal tissues and 3 cell lines (SW1990, PANC-1 and AsPC-1). Moreover, the EIF3C-shRNA lentivirus was constructed to suppress EIF3C expression. Following this, the cell colony formation assay was employed to evaluate proliferation ability of PC cells. Meanwhile, the cell cycle and apoptotic assays were also performed by flow cytometry. We found that level of EIF3C in PC tissues was significantly increased compared with that in adjacent normal tissues. Furthermore, the knockdown of EIF3C can significantly reduce cell proliferation, block cell cycle in G2/M and induce apoptosis in both SW1990 and PANC-1 cells. Our findings suggest that EIF3C plays a crucial role in the progression of PC and may be a potential target in the treatment of PC. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in human epithelial carcinomas of multiple organs including the pancreas, but its functional role in carcinoma development has not yet been fully clarified. The aim of this study was to investigate the role of CD109 in the malignancy of pancreatic ductal adenocarcinoma (PDAC). PDAC specimens of 145 cases were immunostained for CD109, and correlations between CD109 expression and clinicopathological conditions were analyzed. CD109 expression in PANC-1 cells, a PDAC-derived cell line, was decreased by siRNA or shRNA and its effect on the malignancy of PANC-1 cells was examined. Suppression of CD109 expression in PANC-1 cells resulted in reduction of in vitro cell motility and tumorigenicity in xenografts. Based on these results, we investigated the relationship between CD109 expression and metastasis of PDAC using tumor tissue specimens. Among 106 recurrent cases of 145 PDAC, there was a tendency for CD109-positive cases to be accompanied by distant metastasis. CD109 plays a critical role in the promotion of tumorigenic ability and cellular motility relating to metastasis of PDAC cells. [ABSTRACT FROM AUTHOR]

Development of novel methods is needed for the synthesis of nanoparticles. Attention on such particles has elevated disquiet about the eco-friendly manner of their fabrication methods. In the present study, we equipped and synthesized gold nanoparticles (AuNPs) from Panax notoginseng; investigated as an environmentally friendly and non-toxic substrate. Amalgamation of AuNPs was distinguished by numerous studies such as UV-absorbance and it shows peak values in the range of 520–550 nm. Nanoparticles sizes are confirmed by dynamic light scattering analysis and it shows 100 nm. Moreover, transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDX) confirmed the shape of the Au particles present in the synthesized materials. FTIR analysis studies showed the active molecules positioned in the plane of the synthesized particles. The anticancer potential of AuNPs was evaluated in PANC-1 cells. Additionally, AuNPs efficiently induced cytotoxicity, ROS and apoptosis by intonating intrinsic apoptotic gene expressions in PANC-1 cells. Finally, our study confirmed the synthesis of AuNPs from Panax notoginseng, which showed anticancer effects in an environmentally friendly manner. [ABSTRACT FROM AUTHOR]

Individuals diagnosed with cancer often turn to the use of herbal remedies with the intention of treating and ameliorating the condition, impeding the progression of metastasis, enhancing immune function, mitigating stress, and inducing relaxation. Recently, medicinal plants were combined with conventional chemotherapy to decrease the side effects and increase the effectiveness of chemotherapy. This study showed the effectiveness of gemcitabine (Gem) was significantly increased after being used together with ethyl acetate extract obtained from Vernonia amygdalina (Eav) leaves. The combination doses of Eav and Gem were determined based on cytotoxic activity using the MTT assay method. The anticancer effect of this combination was identified by several parameters including the apoptosis effect, anti-migration, and anti-invasion activities of PANC-1 cells. Furthermore, this effect was explained via protein expression evaluation using immunohistochemical and flow cytometry. The Eav has a better Inhibitory Concentration 50 (IC 50) than Gem of 21.19 ± 0.64 µg/mL and 164.78 ± 1.40 µg/mL. The combination of Eav and Gem at IC 50 (1:1) has the strongest activity than Eav and Gem alone at 500.00 µg/mL. The anti-cancer effect of this combination showed significantly increased levels of apoptosis, particularly in the early phase of 17.46 ± 0.35 % (p < 0.0001) than Eav and Gem alone of 7.76 ± 0.25 % and 7.06 ± 0.20 %. A similar impact was evaluated in the migration and invasion of PANC-1 cells after the combination treatment. The % relative migration and cell invasion were significantly decreased compared to the control group and Eav or Gem alone by 21.49 ± 0.96 % and 125.25 ± 5.25 cells, respectively (p < 0.0001). This study found that signature molecules of VEGF, COX2, RAS, and MEK were down-regulated after treatment. Our study suggested that the Eav ameliorates the Gem effect against PANC-1 cells through apoptosis, migration, and invasion influence via RAS/MEK pathways. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is an aggressive disease that progresses in a relatively symptom-free manner; thus, is difficult to detect and treat. Essential oil is reported to exhibit pharmacological properties, besides its common and well-known function as aromatherapy. Therefore, this study herein aimed to investigate the anti-proliferative effect of essential oil extracted from leaves of Garcinia atroviridis (EO-L) against PANC-1 human pancreatic cancer cell line. The cell growth inhibitory concentration at 50% (IC50) and selective index (SI) values of EO-L analyses were determined as 78 µg/mL and 1.23, respectively. Combination index (CI) analysis revealed moderate synergism (CI values of 0.36 to 0.75) between EO-L and 2 deoxy-d-glucose (2-DG) treatments. The treatments of PANC-1 cells with EO-L, 2-DG and EOL+2DG showed evidence of depolarization of mitochondrial membrane potential, cell growth arrest and apoptosis. The molecular mechanism causing the anti-proliferative effect between EO-L and 2-DG is potentially through pronounced up-regulation of P53 (4.40-fold), HIF1α (1.92-fold), HK2 (2.88-fold) and down-regulation of CYP3A5 (0.11-fold), as supported by quantitative mRNA expression analysis. Collectively, the current data suggest that the combination of two anti-proliferative agents, EO-L and 2-DG, can potentially be explored as therapeutic treatments and as potentiating agents to conventional therapy against human pancreatic cancer.

Individuals diagnosed with cancer often turn to the use of herbal remedies with the intention of treating and ameliorating the condition, impeding the progression of metastasis, enhancing immune function, mitigating stress, and inducing relaxation. Recently, medicinal plants were combined with conventional chemotherapy to decrease the side effects and increase the effectiveness of chemotherapy. This study showed the effectiveness of gemcitabine (Gem) was significantly increased after being used together with ethyl acetate extract obtained from Vernonia amygdalina (Eav) leaves. The combination doses of Eav and Gem were determined based on cytotoxic activity using the MTT assay method. The anticancer effect of this combination was identified by several parameters including the apoptosis effect, anti-migration, and anti-invasion activities of PANC-1 cells. Furthermore, this effect was explained via protein expression evaluation using immunohistochemical and flow cytometry. The Eav has a better Inhibitory Concentration 50 (IC 50 ) than Gem of 21.19 ± 0.64 µg/mL and 164.78 ± 1.40 µg/mL. The combination of Eav and Gem at IC 50 (1:1) has the strongest activity than Eav and Gem alone at 500.00 µg/mL. The anti-cancer effect of this combination showed significantly increased levels of apoptosis, particularly in the early phase of 17.46 ± 0.35 % (p < 0.0001) than Eav and Gem alone of 7.76 ± 0.25 % and 7.06 ± 0.20 %. A similar impact was evaluated in the migration and invasion of PANC-1 cells after the combination treatment. The % relative migration and cell invasion were significantly decreased compared to the control group and Eav or Gem alone by 21.49 ± 0.96 % and 125.25 ± 5.25 cells, respectively (p < 0.0001). This study found that signature molecules of VEGF, COX2, RAS, and MEK were down-regulated after treatment. Our study suggested that the Eav ameliorates the Gem effect against PANC-1 cells through apoptosis, migration, and invasion influence via RAS/MEK pathways., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

An L-fucose specific lectin from pathogenic fungus Aspergillus niger isolated from the corneal smears of keratitis patient was purified in a single step using mucin coupled sepharose-4B column by 58-fold. The purified lectin, ANL has molecular mass of 30 kDa by SDS–PAGE and 31.6 kDa by ESI-MS. ANL is a glycoprotein with 2.59% carbohydrate. ANL is blood group nonspecific and also agglutinates rabbit erythrocytes. ANL is heat stable up to 50 °C and over a pH range of 7–10. Hapten inhibition studies revealed that ANL is specific to L-fucose, galactose, lactose and glycoproteins, showing highest MIC of 3.125 μg for L-fucose, mucin and fetuin. ANL has potent antibacterial activity against Klebsiella pneumoniae , Staphylococcus aureus , Pseudomonas aeruginosa and Escherichia coli and also it inhibits the biofilm formation by them. ANL showed strong binding to human pancreatic adenocarcinoma PANC-1 cells which was effectively blocked by L-fucose and mucin respectively by 76.2% and 84.2%. ANL showed dose and time dependent growth inhibitory effect on PANC-1 cells with IC 50 of 1.25 μg/ml at 48 h. Effect of ANL was compared with another fucose specific lectin AOL, from Aspergillus oryzae showing an IC 50 of 1.85 μg/ml at 48 h revealing promising clinical potential of ANL. [ABSTRACT FROM AUTHOR]

Summary: The high fatality and morbidity of pancreatic cancer have remained almost unchanged over the last decades and new clinical therapeutic tools are urgently needed. We determined the cytotoxic activity of aminosteroid derivatives RM-133 (androstane) and RM-581 (estrane) in three human pancreatic cancer cell lines (BxPC3, Hs766T and PANC-1). In PANC-1, a similar level of antiproliferative activity was observed for RM-581 and RM-133 (IC50 = 3.9 and 4.3 μM, respectively), but RM-581 provided a higher selectivity index (SI = 12.8) for cancer cells over normal pancreatic cells than RM-133 (SI = 2.8). We also confirmed that RM-581 induces the same ER stress-apoptosis markers (BIP, CHOP and HERP) than RM-133 in PANC-1 cells, pointing out to a similar mechanism of action. Finally, these relevant in vitro results have been successfully translated in vivo by testing RM-581 using different doses (10–60 mg/kg/day) and modes of administration in PANC-1 xenograft models, which have led to tumor regression without any sign of toxicity in mice (animal weight, behavior and histology). Interestingly, RM-581 fully reduced the pancreatic tumor growth when administered orally in mice. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 6-methoxy-5,6-dihydrochelerythrine is a alkaloid extracted from Radix zanthoxyli. • MDC can inhibit cell proliferation and induce apoptosis of PANC-1 cells. • MDC can inhibit migration and invasion of PANC-1 cells. • MDC can down-regulate the Ras/Raf/Mek/Erk pathway of PANC-1 cells. Abstract To investigate the suppression of PANC-1 pancreatic cancer cells by 6-methoxy-5,6-dihydrochelerythrine (MDC), which is a novel natural product from Radix zanthoxyli, and its underlying mechanism. PANC-1 cells were treated with MDC. Cell proliferation, cell cycle, apoptosis and cell migration or invasion abilities were measured by MTT, flow cytometry assays and invasion assays, respectively. The expression of Ras protein and the inhibition of the downstream Raf/Mek/Erk signalling pathway were measured by western blot. The results showed that MDC can inhibit the cell viability and induce the apoptosis of PANC-1 cells. MDC could inhibit the cell migration or invasion of PANC-1 cells, down-regulate the expression of the Ras protein and inhibit the downstream Raf/Mek/Erk pathway in PANC-1 cells. MDC can inhibit the cell proliferation, apoptosis, migration and invasion abilities of PANC-1, which may be related to the regulation of Ras and its downstream Raf/Mek/Erk signalling pathway. [ABSTRACT FROM AUTHOR]

Preclinical Research & Development Pancreatic cancer is the third leading cause of death in the US with a poor 5‐year survival rate of 8.5%. A novel anti‐cancer drug, dimethylamino parthenolide (DMAPT), is the water‐soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the Nuclear chain factor kappa‐light‐chain enhancer of activated B cells (NFκB) pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress‐induced cell death. Actinomycin‐D (ActD) is a polypeptide antibiotic that binds to DNA, and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that ActD could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and ActD would result in synergistic inhibition of Panc‐1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by ActD, via phosphorylation of c‐Jun, by minimizing NFκB inhibition of c‐Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: ActD (1,200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou‐Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/ActD of 12/0.01 and 18/0.015 μM, respectively. [ABSTRACT FROM AUTHOR]

Recombinant Lampetra japonica RGD peptide (rLj-RGD3) is a soluble toxin protein with three RGD (Arg-Gly-Asp) motifs and a molecular weight of 13.5 kDa. The aim of this study was to investigate the effects and mechanisms of rLj-RGD3 on tumor growth and survival in pancreatic carcinoma Panc-1 cell-bearing mice. A Panc-1 human pancreatic carcinoma-bearing nude mouse model was successfully generated, and the animals were treated with different doses of rLj-RGD3 for 3 weeks. The volume and weight of the subcutaneous tumors, the survival of the nude mice, histopathological changes, the intratumoral MVD, the number of apoptotic Panc-1 cells, and apoptosis-related proteins and gene expressions were determined. rLj-RGD3 significantly decreased the tumor volumes and weights, and the maximum tumor volume and weight IR values were 53.2% (p < 0.001) and 55.9% (p < 0.001), respectively. The life expectancy of Panc-1-bearing nude mice treated with rLj-RGD3 was increased by 56.3% (p < 0.001). Meanwhile, rLj-RGD3 promoted the expression of Bax, caspase-3, and caspase-9 and inhibited Bcl-2 and VEGF expression. In addition, rLj-RGD3 did not change FAK, PI3K and Akt expression, but p-FAK, p-PI3K and p-Akt, levels were down-regulated. These results show that rLj-RGD3 induced potent anti-tumor activity in vivo and suppressed the growth of transplanted Panc-1 cells in a nude mouse model, implying that rLj-RGD3 may serve as a potent clinical therapeutic agent for human pancreatic carcinoma. [ABSTRACT FROM AUTHOR]

Disconnection of a cell from its epithelial neighbours and the formation of a mesenchymal phenotype are associated with profound changes in the distribution of cellular components and the formation of new cellular polarity. We observed a dramatic redistribution of inositol trisphosphate receptors (IP3Rs) and stromal interaction molecule 1 (STIM1)-competent endoplasmic reticulum-plasma membrane junctions (ER-PM junctions) when pancreatic ductal adenocarcinoma (PDAC) cells disconnect from their neighbours and undergo individual migration. In cellular monolayers IP3Rs are juxtaposed with tight junctions. When individual cells migrate away from their neighbours IP3Rs preferentially accumulate at the leading edge where they surround focal adhesions. Uncaging of inositol trisphosphate (IP3) resulted in prominent accumulation of paxillin in focal adhesions, highlighting important functional implications of the observed novel structural relationships. ER-PM junctions and STIM1 proteins also migrate to the leading edge and position closely behind the IP3Rs, creating a stratified distribution of Ca2+ signalling complexes in this region. Importantly, migration of PDAC cells was strongly suppressed by selective inhibition of IP3Rs and store-operatedCa2+ entry (SOCE), indicating that these mechanisms are functionally required for migration. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the cytotoxic activity of tetrahydrocorysamine (TCSM) from Corydalis Rhizoma W. T. Wang (Papaveraceae) against PANC-1 cells and its possible mechanisms. Methods: TCSM was isolated from Corydalis Rhizoma by column chromatography and identified by mass spectrometry and nuclear magnetic resonance (NMR). The effects of TCSM on the proliferation and apoptosis of PANC-1 cells were determined by methyl thiazolyl tetrazolium (MTT) and flow cytometry assays. The effect of TCSM on the expressions of mitochondria-mediated apoptotic proteins were investigated by Western blot assay. Xenograft assay was used to evaluate the anticancer activity of TCSM in vivo. Results: TCSM showed cytotoxic activity against PANC-1 cells with half-maximal concentration (IC50) of 19.16 μM in MTT assay. TCSM (5, 10 and 20 μM) significantly (p < 0.01) increased the apoptosis rates of PANC-1 cells (24.45, 35.26 and 54.16 vs 6.12 %), compared with control group. The results of Western blot suggest that TCSM significantly (p < 0.01) down-regulated the expressions of anti- apoptotic proteins (Bcl-2 and Survivin), up-regulated the expressions of pro-apoptotic proteins (Bax, Smac, c-caspase-3 and c-caspase-9) and promoted the release of cytochrome C from mitochondria to the cytoplasm of PANC-1 cells, compared with control. TCSM (20 mg/kg) significantly (p < 0.01) inhibited the growth of PANC-1 cell-induced tumor (384 vs 1138 mm3) by regulating the expressions of mitochondria-mediated apoptotic proteins as stated above for xenograft assay, compared with control. Conclusion: TCSM induces apoptosis in PANC-1 cells in vitro and in vivo via mitochondria-mediated apoptotic pathway. [ABSTRACT FROM AUTHOR]

Previous population investigations have suggested that the application of curcumin may be associated with decreased incidence and improved prognosis in certain types of cancer. Forkhead box O1 (FOXO1) has been implicated in the regulation of several biological processes, including stress resistance, metabolism, DNA repair, cell cycle and apoptosis. The aims of the present study were to investigate the effects and molecular mechanisms of curcumin on the induction of anti-proliferation, cell cycle arrest and apoptosis, by FOXO1, in pancreatic cancer cells. The MTT assay and ELISA-Brdu assay were used to assess cell proliferation. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were used to detect the expression of PCNA, Ki-67, B-cell lymphoma-2 (Bcl-2), B-cell-associated X protein (Bax), cyclin D1, p21, p27 and FOXO1. Cell apoptosis was detected using a Cell Death ELISA detection kit. A Caspase-3/9 Fluorescent Assay kit was used to detect caspase activity. The findings revealed that curcumin significantly decreased cell proliferation, which was associated with increased expression of the p21/CIP1 and p27/KIP1 cyclin-dependent kinase inhibitors, and inhibited expression of cyclin D1. In addition, curcumin induced apoptosis by decreasing the Bcl-2/Bax protein ratio and increasing caspase-9/3 activation in the pancreatic cancer cells. Using siRNA against FOXO1, and Akt inhibitor and activator, the present study confirmed that curcumin induced the expression of FOXO1 by inhibition of phosphoinositide 3-kinase/Akt signaling, leading to cell cycle arrest and apoptosis. In conclusion, these findings offer support for a mechanism that may underlie the anti-neoplastic effects of curcumin and justify further investigation to examine the potential roles for activators of FOXO1 in the prevention and treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

In this study, a novel concise series of molecules based on the structure of goniothalamin ( 1 ) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC 50 value (2.7 μM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin ( 1 ). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin ( 1 ) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 μM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • DRE-induced PANC-1 cells apoptosis was investigated. • DRE inhibited the proliferation and induced the apoptosis of PANC-1 cells. • FTIR microspectroscopy reflected biomacromolecular changes during apoptosis. • PCA further revealed significant changes in protein content/structure. • The study may provide new insights into DRE-induced PNAC-1 cells apoptosis. Pancreatic cancer seriously threatens human health and life. Dandelion root extract (DRE) has a good inhibitory effect on pancreatic cancer cells, however, its mechanism is not clear up to now. Fourier transform infrared (FTIR) microspectroscopy can detect biomacromolecular changes sensitively. In this study, FTIR microspectroscopy was used to investigate pancreatic cancer PNAC-1 cells apoptosis induced by DRE. The shift of amide I and principal component analysis (PCA) indicated the significant changes in proteins while peak-area ratios showed the changes of biomacromolecular structure and content. This study may provide new insights into DRE-induced apoptosis of PNAC-1 cells, which also suggests that FTIR microspectroscopy may be a potential tool for apoptotic study. [ABSTRACT FROM AUTHOR]

Simple Summary: Potassium channels permit the selective passage of K+ ions across the cell me brane and are important for setting the membrane potential and for the transmission of electrical signals in all cells. Ca2+ activated K+ channels provide a means to couple intracellular calcium signaling to changes of the membrane potential. Among these, the large-conductance Ca2+-activated K+ channel, known as BK, has been proposed to be involved in several cancer-associated processes. In the present work, we tested various BK channel activators for anti-cancer effects in melanoma and pancreatic duct carcinoma cell lines. Only one of the activators (NS-11021) had effects on cancer-associated processes. However, the compound, as a side-effect, also increased the intracellular Ca2+ concentration independently of BK channel activation. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects. Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca2+-activated K+ channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents. [ABSTRACT FROM AUTHOR]

Objective To observe the influence of melatonin on the PANC-1 cell proliferation and to investigate its mechanism. Methods PANC-1 cells were treated with different concentrations of melatonin, and MTT method was used to detect the proliferation of PANC-1 cells and to calculate the proliferation rate. Western blotting was used to detect the expression of active fragment of Notch 1 (NICD1) in PANC-1 cells. Results The proliferation rate of the control group 1 was 0.38%±0.03%, after adding the concentration of 1, 1 000 and 1 000 000 nmol/L melatonin, the proliferation rates of PANC-1 cells were 0.36%±0.02%, 0.32%±0.02%and 0.26%±0.01%, respectively. Significant difference was found between the control group 1 and the melatonin groups with concentrations of 1 000 and 1 000 000 nmol/L melatonin (all P<0.05). The proliferation rate of the control group 2 was 0.43%±0.02%, the proliferation rate in the DAPT group was 0.30%±0.02%(P<0.05). The expression of NICD1 in the control group 1 was 0.47 ±0.05. After adding the concentrations of 1, 1 000 and 1 000 000nmol/L melatonin, the expression of NICD1 was 0.32 ±0.04, 0.33 ±0.05 and 0.21 ±0.03, respectively. Significant difference in the NICD1 expression was found between the control group 1 and the melatonin groups with concentrations of 1 000 and 1 000 000 nmol/L melatonin (all P<0.05). The expression of NICD1 in the control group 2 was 0.63 ±0.05. The expression of NICD1 in the DAPT group was 0.38 ±0.03 (P<0.05). Conclusion Melatonin can inhibit the proliferation of PANC-1 cells, whose mechanism may be involved in regulating the Notch signaling pathway . [ABSTRACT FROM AUTHOR]

Introduction: Suppressing the phenotype of cancer stem cells (CSCs) is a promising treatment strategy for cancer. P38 mitogen-activated protein kinases (MAPK, p38) play an important role in the occurrence, development, and stemness maintenance of tumors. The aim of the current study was to investigate the effect of p38 on the stemness maintenance of CSCs in pancreatic cancer cell line PANC-1., Material and Methods: PANC-1 human pancreatic cancer cells were treated with 5-fluorouracil (5-FU) at 0.5 IC50, IC50, and 2 IC50 for 24 h. PANC-1 cells were treated for 24 h with 5-FU at 0.5IC50, IC50, and 2IC50 with or without VX-702, p38 phosphorylation inhibitor. Cells were resuspended in DMEM supplemented with 20 ng/ml epidermal growth factor, 2% B27, 5 mg/ml insulin, 20 g/ml basic fibroblast growth factor, and 10 μg/ml transferrin. Cells were seeded in ultra-low adhesion 6-well dishes to observe tumor spheroidization. The expression of CDK2, cyclin B1, cyclin D1, OCT4, SOX2, Nanog, and p38 was measured by Western blot. The mRNA expression of p38, OCT4, Nanog, and SOX2 was measured by RT-PCR. Flow cytometry was performed to evaluate the cell cycle, apoptosis, and proportion of CD44+CD133+ PANC-1 cells., Results: 5-FU decreased cell viability and increased apoptosis. 5-FU suppressed the stemness maintenance of CSCs in PANC-1 cells, as demonstrated by the inhibition of tumorsphere formation, the decrease in CD44+CD133+ cells' fraction, and downregulation of OCT4, Nanog, and SOX2 expression. In addition, 5-FU inhibited the phosphorylation of p38 in PANC-1 cells. The phosphorylation of p38 was subsequently suppressed by VX-702, p38 mitogen-activated protein kinase inhibitor, which exhibited similar effects as those of 5-FU treatment. The effect of VX-702 on PANC-1 cells was further enhanced by 5-FU treatment. Thus, p38 inhibitor decreased the viability and increased the apoptosis of PANC-1 cells. P38 inhibitor suppressed the stemness maintenance of CSCs in PANC-1 cells, as demonstrated by the inhibition of tumorsphere formation, the decrease in CD44+CD133+ cells, and the downregulation of OCT4, Nanog, and SOX2 expression., Conclusions: These findings indicate that the inhibition of p38 phosphorylation suppresses the stemness maintenance and 5-FU resistance of PANC-1 cells, providing a potential therapeutic target for the prevention and treatment of pancreatic cancer.

The present study aimed to determine the anticancer effect of the herbal mixture extract C5E in the pancreatic cancer cell line, PANC-1, in the absence or presence of gemcitabine treatment, a chemotherapeutic drug used for the treatment of pancreatic cancer. The anticancer effects of C5E, gemcitabine and C5E plus gemcitabine in PANC-1 cells following 72 h of treatment were investigated. The effect of each treatment on cell cycle arrest, apoptosis and the proportion of side population (SP) cells was determined using flow cytometric analysis following propidium iodide (PI), Annexin V-FITC/PI double staining and Hoechst 33342 staining, respectively. SP cells share similar characteristics to cancer stem-like cells, and a reduction in the SP is considered to be indicative of an anticancer effect. The percentage of SP cells and the cell viability of general PANC-1 cells were significantly decreased in response to all treatments. The percentage of SP cells was reduced from 8.2% (control) to 3.9, 7.2 and 5.1% following the treatment with C5E, gemcitabine and the co-treatment, respectively. All three treatments were discovered to inhibit cell viability by arresting the cell cycle at the S phase and promoted cell death by inducing early apoptosis, with the levels of apoptosis being increased from 1.9% (control) to 7.3, 2.5 and 12.0% following the treatment with C5E, gemcitabine and the co-treatment, respectively. The mRNA expression levels of sonic hedgehog, which is implicated in the development of certain types of cancer, were downregulated to a greater extent following the co-treatment with C5E and gemcitabine compared with the treatment with either C5E or gemcitabine alone. As the co-treatment with gemcitabine and C5E was more effective than each individual treatment, the present study suggested that the combined treatment may exhibit synergistic effects in PANC-1 cells. [ABSTRACT FROM AUTHOR]

Pancreatic cancer ranks seventh in terms of cancer‑related mortality in men and women worldwide, where the most common subtype is pancreatic ductal adenocarcinoma (PDAC). To date, the pathogenesis of PDAC remains incompletely understood and the prognosis of PDAC is poor. In the present study, the expression of interleukin‑28 receptor α subunit (IL‑28RA) in PDAC tissues was detected using immunofluorescence staining and western blotting. IL‑28RA recombinant plasmids and control pCMV6‑entrymammalian expression plasmid, short hairpin (sh)IL‑28RA plasmids and control pRS scrambled shRNA vector purchased were used to produce stably transfected PANC‑1 cells overexpressing IL‑28RA or with IL‑28RA expression knocked down. MTS assays were used to measure cell viability and wound healing assay was used to assess the cell migratory ability in vitro . Flow cytometry analysis was performed to determine the proportion of cells in each phase of the cell cycle whereas total protein and phosphorylated protein levels were assessed using western blotting. Xenograft models of subcutaneous tumors were established by injecting PANC‑1 cells hypodermically into nude mice to investigate the effect of IL‑28RA on tumorigenesis and tumor growth. The results showed that the expression of IL‑28RA in PDAC tissues was lower compared with that in normal tissues. IL‑28RA overexpression in vitro resulted in the activation of the IL‑28RA pathway, which reduced cell viability and decreased the proportion of cells in the G 2 /M phase by reducing cyclin B1 expression. In addition, IL‑28RA overexpression inhibited migration of PDAC cells. By contrast, an increased proportion of cells in G 2 /M phase, upregulated cyclin B1 expression and enhanced cell viability and migratory ability along with inhibition of the IL‑28RA pathway were observed in PANC‑1 cells following IL‑28RA knockdown. The inhibitory effect of IL‑28RA was observed by tumor size in a nude mouse model induced by PANC‑1 cells with stable IL‑28RA overexpression or knockdown. The tumor size induced by PANC‑1 cells with stable IL‑28RA overexpression were smaller, whilst larger tumors induced by PANC‑1 cells were observed following stable IL‑28RA knockdown, when compared to control. Further studies showed that the effect of IL‑28RA on PDAC cells was exerted by regulating the phosphorylation levels of STAT1 and AKT. In conclusion, lower IL‑28RA expression may contribute to the pathogenesis of PDAC, where results from the present may provide further insights into the progression of PDAC, in addition to highlighting potentially novel therapeutic targets for this disease.

The utilization of natural compounds as therapeutic agents to treat pancreatic cancer has recently focused on natural drug research. Calotropis gigantea has long been believed to be a medicinal plant that helps in treating various diseases. The bioactive compounds 9-metoxipinoresinol and isoliquiritigenin isolated from C. gigantea leaves are proven to act as therapeutic agents by inhibiting the cancer cell growth of Panc-1 cells. This study aimed to screen the potential molecular inhibition mechanisms of 9-metoxipinoresinol and isoliquiritigenin against pancreatic cancer development in-silico . We analyzed the activity of the aforementioned two compounds as inhibitors of several proteins that play a role in the growth of pancreatic cancer cells, such as GCNT3, GOT1, c-Met, PPARγ, BUB1, and NF-κβ, through molecular docking investigation. Our data suggested that 9-metoxipinoresinol and isoliquiritigenin were able to have well interaction with the target proteins, in which the predicted affinity energy ranged between -6.8 and 8.7 kcal/mol. The docking scores of 9-metoxipinoresinol and isoliquiritigenin were higher than the standard drug used (gemcitabine). Based on the binding affinity energy, GCNT3 and BUB1 are potentially to be used as target molecules for cancer therapy using 9-metoxipinoresinol and isoliquiritigenin, respectively., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Author(s).)

Background: Pancreatic adenocarcinoma (PAAD) has a high rate of mortality. Unfortunately, it is difficult to diagnosis. This study aimed to develop a more in-depth understanding of the disease., Methods: A total of 177 patients with PAAD were recruited from The Cancer Genome Atlas (TCGA) database. Microarray analysis was performed to identify differentially expressed genes (DEGs) in PAAD. The microarray data were adapted to the ingenuity pathway analysis (IPA) for annotation and visualization, followed by protein-protein interaction (PPI) network analysis. In vitro transwell migration assays were conducted to explore the molecular and functional characteristics of pancreatic adenocarcinoma cells (PANC-1) with stable low expression of G-protein signaling modulator 2 ( GPSM2 ). Expression of GPSM2 and the associated hub genes were detected by reverse transcription-quantitative polymerase chain reaction (qPCR)., Results: The overexpression of GPSM2 was proved in PAAD, as compared with the healthy tissues, as well as its correlation with history of chronic pancreatitis, T stage, TNM stage and tumor grade. We described it as an independent prognostic factor and found that it could influence the infiltration of immune cells in the tumor microenvironment. Silencing of GPSM2 restrained the and migration of the cells. Microarray analysis identified 1,631 DEGs in PAAD cells. The PPI network analysis identified hub genes including CD44 , ITGB1 , ITGB5 , ITGA2 , ITGA5 , AKT1 , EGFR , NRAS and MAP2K1 , and their relationship with GPSM2 was confirmed by qPCR., Conclusions: GPSM2 is a novel prognostic factor and therapeutic target for PAAD. GPSM2 promoted the migration of pancreatic adenocarcinoma cells .Targeting GPSM2 and its downstream genes may prolong the survival time of patients with PAAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-224). The authors have no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

Increasing evidence shows that eukaryotic initiation factor subunit (EIF3C) plays a crucial role in development of tumors. However, the underlying roles of EIF3Cin the development of pancreatic cancer (PC) remain unknown. In this study, we examined the expression of EIF3C in PC tissues, their adjacent normal tissues and 3 cell lines (SW1990, PANC-1 and AsPC-1). Moreover, the EIF3C-shRNA lentivirus was constructed to suppress EIF3C expression. Following this, the cell colony formation assay was employed to evaluate proliferation ability of PC cells. Meanwhile, the cell cycle and apoptotic assays were also performed by flow cytometry. We found that level of EIF3C in PC tissues was significantly increased compared with that in adjacent normal tissues. Furthermore, the knockdown of EIF3C can significantly reduce cell proliferation, block cell cycle in G2/M and induce apoptosis in both SW1990 and PANC-1 cells. Our findings suggest that EIF3C plays a crucial role in the progression of PC and may be a potential target in the treatment of PC., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Regulated cell death by way of ferroptosis involves iron-dependent accumulation of cellular reactive oxygen species (ROS). Ferroptosis is attracting attention as a potential therapeutic target for cancer treatments without drug resistance. The relationship between irisin, a myokine involved in autophagy and ROS metabolism, and ferroptosis is unclear. In this study, we used erastin-induced ferroptosis in PANC-1 cells to examine potential interactions of irisin with ferroptosis. Using western blots and reverse transcriptase polymerase chain reactions, we found that irisin can further exacerbate erastin-induced upregulation in free iron, lipid ROS levels, and glutathione depletion, relative to cells treated with erastin only. Conversely, removal of irisin limited erastin effects. Furthermore, irisin modulation of ferroptosis was associated with the expression changes in molecules important for ROS metabolism, iron metabolism, and the cysteine/glutamate antiporter system (system X c - ). These study findings suggest that irisin can act as a master factor of ferroptosis, and that potential implications for harnessing irisin-mediated ferroptosis for cancer treatment are warranted., (© 2020 The Authors.)

Background: Accumulating evidence indicates that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in human epithelial carcinomas of multiple organs including the pancreas, but its functional role in carcinoma development has not yet been fully clarified. The aim of this study was to investigate the role of CD109 in the malignancy of pancreatic ductal adenocarcinoma (PDAC)., Methods: PDAC specimens of 145 cases were immunostained for CD109, and correlations between CD109 expression and clinicopathological conditions were analyzed. CD109 expression in PANC-1 cells, a PDAC-derived cell line, was decreased by siRNA or shRNA and its effect on the malignancy of PANC-1 cells was examined., Results: Suppression of CD109 expression in PANC-1 cells resulted in reduction of in vitro cell motility and tumorigenicity in xenografts. Based on these results, we investigated the relationship between CD109 expression and metastasis of PDAC using tumor tissue specimens. Among 106 recurrent cases of 145 PDAC, there was a tendency for CD109-positive cases to be accompanied by distant metastasis., Conclusions: CD109 plays a critical role in the promotion of tumorigenic ability and cellular motility relating to metastasis of PDAC cells., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Circulating microvesicles are able to mediate long-distance cell-cell communications. It is essential to understand how microvesicles from pancreatic cancer act on other cells in the body. In this work, serum-derived microvesicles were isolated from 10 patients with locally advanced pancreatic cancer and healthy controls. Using Cell Transwell and WST-1 reagents, we found that microvesicles from pancreatic cancer accelerated migration and proliferation of PANC-1 cells. Meanwhile, the proliferation of these cancer-microvesicle-treated cells (CMTCs) was affected less by 10 μM of gemcitabine relative to healthy microvesicle-treated cells (HMTCs). Next, we optimized the filter-aided sample preparation method to increase the recovery of protein samples and then applied it to the quantification of the proteome of CMTCs and HMTCs. The peptides were labeled and analyzed by liquid chromatography-tandem mass spectrometry. In total, 4102 proteins were identified, where 35 proteins were up-regulated with 27 down-regulated in CMTCs. We verified the quantitative results of three key proteins CD44, PPP2R1A, and TP53 by Western blot. The Ingenuity Pathway Analysis revealed pathways that cancer microvesicles might participate in to promote cell migration and proliferation. These findings may provide novel clues of treatment for tumorigenesis and metastasis.

Background/aim: Pancreatic cancer is a disease with very poor prognosis, and none of currently available pharmacotherapies have proven to be efficient in this indication. The aim of this study was to analyze the expression of fatty acid synthase (FASN) gene as a potential therapeutic target in proliferating human pancreatic cancer cells (PANC-1), and verify if orlistat, originally developed as an anti-obesity drug, inhibits PANC-1 proliferation., Materials and Methods: The effects of orlistat on gene expression, lipogenesis, proliferation and apoptosis was studied in PANC-1 cell culture., Results: Expression of FASN increased during proliferation of PANC-1. Inhibition of FASN by orlistat resulted in a significant reduction of PANC-1 proliferation and enhanced apoptosis of these cells., Conclusion: This study showed, to our knowledge for the first time, that orlistat exhibits significant antitumor activity against PANC-1 cells. This implies that orlistat analogs with good oral bioavailability may find application in pharmacotherapy of pancreatic cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Disconnection of a cell from its epithelial neighbours and the formation of a mesenchymal phenotype are associated with profound changes in the distribution of cellular components and the formation of new cellular polarity. We observed a dramatic redistribution of inositol trisphosphate receptors (IP3Rs) and stromal interaction molecule 1 (STIM1)-competent endoplasmic reticulum-plasma membrane junctions (ER-PM junctions) when pancreatic ductal adenocarcinoma (PDAC) cells disconnect from their neighbours and undergo individual migration. In cellular monolayers IP3Rs are juxtaposed with tight junctions. When individual cells migrate away from their neighbours IP3Rs preferentially accumulate at the leading edge where they surround focal adhesions. Uncaging of inositol trisphosphate (IP3) resulted in prominent accumulation of paxillin in focal adhesions, highlighting important functional implications of the observed novel structural relationships. ER-PM junctions and STIM1 proteins also migrate to the leading edge and position closely behind the IP3Rs, creating a stratified distribution of Ca(2+) signalling complexes in this region. Importantly, migration of PDAC cells was strongly suppressed by selective inhibition of IP3Rs and store-operated Ca(2+) entry (SOCE), indicating that these mechanisms are functionally required for migration., (© 2016 Authors.)