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The article provides updated information on a study that aims to detect and differentiate between pancreatic neuroendocrine tumors (PanNET) and small intestinal neuroendocrine tumors (SI-NET). The correction addresses errors in the previous publication and provides more accurate information on the study's findings. The article includes tables that present the performance metrics of two models, which use various plasma biomarkers and chromogranin A (CgA) to predict the type of tumor. The top biomarkers used in the models are listed. [Extracted from the article]

Objective: To explore the impact of inflammatory factors on the incidence of cerebral small vessel disease (CSVD), we performed a mendelian randomization (MR) study to analyze the causal relationship between multiple inflammatory factors and CSVD imaging markers and utilized summary‐data‐based mendelian randomization (SMR) analysis to infer whether the impact of instrumental variables (IVs) on disease is mediated by gene expression or DNA methylation. Methods: Using public databases such as UKB and IEU, and original genome‐wide association studies, we obtained IVs related to exposure (inflammatory factors) and outcome (CSVD imaging markers). We performed the inverse variance weighted, weighted median, and MR‐Egger methods to assess causal effects between exposure and outcome in univariate MR analysis. To evaluate their heterogeneity, a series of sensitivity analyses were conducted, including the Cochrane Q test, MR‐Egger intercept test, MR‐Presso, and leave‐one‐out analysis. We also applied mediation and multivariate MR analysis to explore the interactions between positive exposures on the same outcome. Additionally, we conducted the SMR, which utilizes instruments within or near relevant genes in blood or brain tissues, to elucidate the causal associations with CSVD markers. Results: ABO Univariate MR of multiple cohorts revealed that the risk of small vessel stroke (SVS) increases with elevated levels of TNF‐related apoptosis‐inducing ligand (TRAIL, OR, 1.23, 95% CI, 1.08–1.39) and interleukin‐1 receptor‐like 2, (IL‐1RL2, OR, 1.29, 95% CI, 1.04–1.61). IL‐18 was a potential risk factor for extensive basal ganglia perivascular space burden (BGPVS, OR, 1.02, 95% CI, 1.00–1.05). Moreover, the risk of extensive white matter perivascular space burden (WMPVS) decreased with rising levels of E‐selectin (OR,.98, 95% CI,.97–1.00), IL‐1RL2 (OR,.97, 95% CI,.95–1.00), IL‐3 receptor subunit alpha (IL‐3Ra, OR,.98, 95% CI,.97–1.00), and IL‐5 receptor subunit alpha (IL‐5Ra, OR,.98, 95% CI,.97–1.00). Mediation and multivariate MR analysis indicated that E‐selectin and IL‐3Ra might interact during the pathogenesis of WMPVS. SMR estimates showed that TRAIL‐related IVs rs5030044 and rs2304456 increased the risk of SVS by increasing the expression of gene Kininogen‐1 (KNG1) in the cerebral cortex, particularly in the frontal cortex (βsmr =.10, Psmr =.003, FDR =.04). Instruments (rs507666 and rs2519093) related to E‐selectin and IL‐3Ra could increase the risk of WMPVS by enhancing DNA methylation of the gene ABO in blood tissue (βsmr =.01–.02, Psmr =.001, FDR =.01–.03). Conclusion: According to MR and SMR analysis, higher levels of TRAIL increased the risk of SVS by upregulating gene expression of KNG1 in brain cortex tissues. In addition, protective effects of E‐selectin and IL‐3a levels on WMPVS were regulated by increased DNA methylation of gene ABO in blood tissue. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the seventh most frequently diagnosed cancer among women worldwide. Most patients experience recurrence and succumb eventually to resistant disease, underscoring the need for an alternative treatment option. In the presented manuscript, we investigated the effect of the TRAIL‐gene, transfected by an innovative bioinspired lipid vector BSV163/DOPE in the presence or absence of cisplatin, to fight against sensitive and resistant ovarian cancer. We showed that BSV163/DOPE can transfect ovarian cancer cell lines (Caov3, OVCAR3, and our new cisplatin‐resistant, CR‐Caov3) safely and efficiently. In addition, TRAIL‐gene transfection in association with cisplatin inhibited cellular growth more efficiently (nearly 50% in Caov3 cells after the combined treatment, and 15% or 25% by each treatment alone, respectively) owing to an increase in apoptosis rate, caspases activity and TRAIL's death receptors expression. Most importantly, such synergistic effect was also observed in CR‐Caov3 cells demonstrated by an apoptosis rate of 35% following the combined treatment in comparison with 17% after TRAIL‐gene transfection or 6% after cisplatin exposition. These results suggest this combination may have potential application for sensitive as well as refractory ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Background: TRAIL is an anticancer drug that induces cancer cell apoptosis by interacting with death receptors (DRs). However, owing to low cell‐surface expression of DRs, certain colorectal cancer (CRC) cells resist TRAIL‐induced apoptosis. Newcastle disease virus (NDV) infection can elevate DR protein expression in cancer cells, potentially influencing their TRAIL sensitivity. However, the precise mechanism by which NDV infection modulates DR expression and impacts TRAIL sensitivity in cancer cells remains unknown. Methods: Herein, we developed nonpathogenic NDV VG/GA strain‐based recombinant NDV (rNDV) and TRAIL gene‐containing rNDV (rNDV‐TRAIL). We observed that viral infections lead to increased DR and TRAIL expressions and activate signaling proteins involved in intrinsic and extrinsic apoptosis pathways. Experiments were conducted in vitro using TRAIL‐resistant CRC cells (HT‐29) and nonresistant CRC cells (HCT116) and in vivo using relevant mouse models. Results: rNDV‐TRAIL was found to exhibit better apoptotic efficacy than rNDV in CRC cells. Notably, rNDV‐TRAIL had the stronger cancer cell‐killing effect in TRAIL‐resistant CRC cells. Western blot analyses showed that both rNDV and rNDV‐TRAIL infections activate signaling proteins involved in the intrinsic and extrinsic apoptotic pathways. Notably, rNDV‐TRAIL promotes concurrent intrinsic and extrinsic signal transduction in both HCT‐116 and HT‐29 cells. Conclusions: Therefore, rNDV‐TRAIL infection effectively enhances DR expression in DR‐depressed HT‐29 cells. Moreover, the TRAIL protein expressed by rNDV‐TRAIL effectively interacts with DR, leading to enhanced apoptosis in TRAIL‐resistant HT‐29 cells. Therefore, rNDV‐TRAIL has potential as a promising therapeutic approach for treating TRAIL‐resistant cancers. Schematic representation of direct mechanisms of the rNDV‐TRAIL viruses. rNDV containing the TRAIL gene (rNDV‐TRAIL) can stably express the TRAIL gene. Also, rNDV‐TRAIL activates the NF‐кB pathway and induces the secretion of TRAIL. The expressed or induced TRAIL binds to the TRAIL receptor on DR4 or DR5. DR5 promotes TRAIL‐induced apoptotic pathways. The pro‐apoptotic complex is formed. Caspase 8 is cleaved, activates caspase 3, and triggers apoptosis via the extrinsic pathway. Also, caspase 8 induces an intrinsic pathway. The cytochrome C combines with procaspase‐9 to produce apoptosome. Apoptosome triggers caspase 9 followed by the activation of caspase‐3 which leads to ends up to apoptosis. [ABSTRACT FROM AUTHOR]

Background: Tumor necrosis factor‐related apoptosis‐inducing ligand activates apoptotic pathways and could potentially be used in anticancer treatments. However, oral squamous cell carcinoma cells are known to be resistant to tumor necrosis factor‐related apoptosis‐inducing ligand‐induced cell death. It has been previously reported that hyperthermia upregulates tumor necrosis factor‐related apoptosis‐inducing ligand‐induced apoptosis in other cancers. As such, we evaluated whether hyperthermia upregulates tumor necrosis factor‐related apoptosis‐inducing ligand‐mediated apoptosis in a tumor necrosis factor‐related apoptosis‐inducing ligand‐resistant oral squamous cell carcinoma cell line. Methods: The oral squamous cell carcinoma cell line HSC3 was cultured and divided into hyperthermia and control groups. We investigated the antitumor effects of recombinant human tumor necrosis factor‐related apoptosis‐inducing ligand using cell proliferation and apoptosis assays. Additionally, we measured death receptor 4 and 5 levels, and determined death receptor ubiquitination status, as well as E3 ubiquitin ligase targeting of death receptor in both hyperthermia and control groups before recombinant human tumor necrosis factor‐related apoptosis‐inducing ligand administration. Results: Treatment with recombinant human tumor necrosis factor‐related apoptosis‐inducing ligand produced greater inhibitory effects in the hyperthermia group than in the control group. Moreover, death receptor protein expression in the hyperthermia group was upregulated on the cell surface (and overall), although death receptor mRNA was downregulated. The half‐life of death receptor was several hours longer in the hyperthermia group; concomitantly, E3 ubiquitin ligase expression and death receptor ubiquitination were downregulated in this group. Conclusion: Our findings suggested that hyperthermia enhances apoptotic signaling by tumor necrosis factor‐related apoptosis‐inducing ligand via the suppression of death receptor ubiquitination, which upregulates death receptor expression. These data suggest that the combination of hyperthermia and tumor necrosis factor‐related apoptosis‐inducing ligand has implications in developing a novel treatment strategy for oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare vasculopathy, with high morbidity and mortality. The sensitivity of the current european society of cardiology/european respiratory society (ESC/ERS) risk assessment strategy may be improved by the addition of biomarkers related to PAH pathophysiology. Such plasma-borne biomarkers may also reduce time to diagnosis, if used as diagnostic tools in patients with unclear dyspnea, and in guiding treatment decisions. Plasma levels of proteins related to tumor necrosis factor (TNF), inflammation, and immunomodulation were analyzed with proximity extension assays in patients with PAH (n = 48), chronic thromboembolic pulmonary hypertension (PH; CTEPH, n = 20), PH due to left heart failure (HF) with preserved (HFpEF-PH, n = 33), or reduced (HFrEF-PH, n = 36) ejection fraction, HF without PH (n = 15), and healthy controls (n = 20). TNF-related apoptosis-inducing ligand (TRAIL) were lower in PAH versus the other disease groups and controls (p < 0.0082). In receiver operating characteristics analysis, TRAIL levels identified PAH from the other disease groups with a sensitivity of 0.81 and a specificity of 0.53 [area under the curve: 0.70; (95% confidence interval, CI: 0.61-0.79; p < 0.0001)]. In both single (p < 0.05) and multivariable Cox regression models Annexin A1 (ANXA1) [hazard ratio, HR: 1.0367; (95% CI: 1.0059-1.0684; p = 0.044)] and carcinoembryonic antigen-related cell adhesion molecule 8 [HR: 1.0603; (95% CI: 1.0004-1.1237; p = 0.0483)] were significant predictors of survival, adjusted for age, female sex and ESC/ERS-initial risk score. Low plasma TRAIL predicted PAH among patients with dyspnea and differentiated PAH from those with CTEPH, HF with and without PH; and healthy controls. Higher plasma ANXA1 was associated with worse survival in PAH. Larger multicenter studies are encouraged to validate our findings. [ABSTRACT FROM AUTHOR]

The lifespans of proteins range from minutes to years within mammalian tissues. Protein lifespan is relevant to organismal aging, as long‐lived proteins accrue damage over time. It is unclear how protein lifetime is shaped by tissue context, where both cell turnover and proteolytic degradation contribute to protein turnover. We develop turnover and replication analysis by 15N isotope labeling (TRAIL) to quantify protein and cell lifetimes with high precision and demonstrate that cell turnover, sequence‐encoded features, and environmental factors modulate protein lifespan across tissues. Cell and protein turnover flux are comparable in proliferative tissues, while protein turnover outpaces cell turnover in slowly proliferative tissues. Physicochemical features such as hydrophobicity, charge, and disorder influence protein turnover in slowly proliferative tissues, but protein turnover is much less sequence‐selective in highly proliferative tissues. Protein lifetimes vary nonrandomly across tissues after correcting for cell turnover. Multiprotein complexes such as the ribosome have consistent lifetimes across tissues, while mitochondria, peroxisomes, and lipid droplets have variable lifetimes. TRAIL can be used to explore how environment, aging, and disease affect tissue homeostasis. Synopsis: A new 15N metabolic labeling method for parallel quantification of cell and protein turnover rates in mouse tissues illustrates the variable influence of "nature" versus "nurture" on protein turnover rates in vivo. The median proteome turnover rate and the identity of the longest‐ and shortest‐lived proteins vary across tissues.Protein turnover and cell turnover occur at similar rates in proliferative tissues, but protein turnover outpaces cell turnover in less proliferative tissues.Sequence features such as hydrophobicity, disorder, and isoelectric point contribute to protein turnover rate only in less proliferative tissues.Protein and organelle turnover rates remain very different from tissue to tissue even after correcting for cell turnover rates. [ABSTRACT FROM AUTHOR]

Resistance to cancer immunotherapy continues to impair common clinical benefit. Here, we use whole‐genome CRISPR‐Cas9 knockout data to uncover an important role for Tuberous Sclerosis Complex 2 (TSC2) in determining tumor susceptibility to cytotoxic T lymphocyte (CTL) killing in human melanoma cells. TSC2‐depleted tumor cells had disrupted mTOR regulation following CTL attack, which was associated with enhanced cell death. Wild‐type tumor cells adapted to CTL attack by shifting their mTOR signaling balance toward increased mTORC2 activity, circumventing apoptosis, and necroptosis. TSC2 ablation strongly augmented tumor cell sensitivity to CTL attack in vitro and in vivo, suggesting one of its functions is to critically protect tumor cells. Mechanistically, TSC2 inactivation caused elevation of TRAIL receptor expression, cooperating with mTORC1‐S6 signaling to induce tumor cell death. Clinically, we found a negative correlation between TSC2 expression and TRAIL signaling in TCGA patient cohorts. Moreover, a lower TSC2 immune response signature was observed in melanomas from patients responding to immune checkpoint blockade. Our study uncovers a pivotal role for TSC2 in the cancer immune response by governing crosstalk between TSC2‐mTOR and TRAIL signaling, aiding future therapeutic exploration of this pathway in immuno‐oncology. Synopsis: Immunotherapy resistance limits clinical benefit, urging a better mechanistic understanding of resistance pathways and discovery of new therapeutic targets. Lin et al mine genome‐wide CRISPR‐Cas9 screening data and uncover TSC2 as a critical factor protecting tumor cells against cytotoxic T lymphocyte attack. Mining whole‐genome CRISPR‐Cas9 knockout screen data identified TSC2 as a critical protector of tumor sensitivity to CTL killing.TSC2‐depleted cancer cells show disrupted mTORC1/mTORC2 regulation upon CTL attack and enhanced CTL‐induced apoptosis.TSC2 depletion upregulates TRAIL receptor expression and sensitizes melanoma cells to TRAIL‐induced cell death.Melanomas from patients responding to immune checkpoint blockades have a lower TSC2 immune response signature. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) induces death receptor‐mediated extrinsic apoptosis, specifically in cancer cells, and Bid (BH3‐interacting domain death agonist) plays an important role in TRAIL‐induced apoptosis. Ferroptosis is a newly defined form of regulated cell death known to be distinct from other forms of cell death. However, our previous studies have shown that ferroptosis shares common pathways with other types of programmed cell death such as apoptosis. In this study, we investigated the role of Bid in the crosstalk between the ferroptotic agent‐induced endoplasmic reticulum (ER) stress response and TRAIL‐induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with the ferroptosis‐inducing agents artesunate and erastin in combination with TRAIL, TRAIL‐induced activation of caspase‐8 was enhanced, and subsequently, the truncation of Bid was increased. Similar results were observed when ovarian adenocarcinoma OVCAR‐3 cells were treated with the ferroptotic agents in combination with TRAIL. Results from studies with Bid mutants reveal that the truncation of Bid and the presence of intact BH3 domains are critical for synergistic apoptosis. Nonfunctional Bid mutants were not able to activate the mitochondria‐dependent apoptosis pathway, which is required for the conversion of p19 to p17, the active form of caspase‐3. These results indicate that Bid plays a critical role in the crosstalk between the ferroptotic agent‐induced ER stress response and TRAIL‐induced apoptosis. [ABSTRACT FROM AUTHOR]

Identifying novel curative and preventive approaches that can specifically target the osteosarcoma cells (OS) without affecting the normal cells is appreciable. The aim of this study is to investigate the combined effect of chrysin as an apigenin analog with high therapeutic potential and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) on the treatment of Saos‐2 and MG‐63 cells. Cell viability were determined using MTT method. The rate of apoptosis was assessed by enzyme‐linked immunosorbent assay (ELISA) cell death assay and caspase 8 activity assays. The messenger RNA (mRNA) and protein evaluation of candidate genes include Bcl‐2, XIAP, c‐IAP1, c‐IAP2, and c‐FLIP were accomplished before and after the treatment by quantitative real‐time polymerase chain reaction (PCR) and Western blot analysis, respectively. Our results showed that chrysin synergistically increased the cytotoxic effects of TRAIL as follows: Chrysin plus TRAIL > TRAIL > Chrysin. Chrysin could sensitize both cells against the TRAIL‐induced apoptosis, amplify the caspase 8 activity and this outcome is achieved by decreasing the expression levels of antiapoptotic genes. Our findings suggest that Chrysin can sensitize the OS cell lines against TRAIL through induction of the death receptor pathway. Moreover, the combinational therapy of these agents might be the promising therapeutic regimen for improving the clinical efficacy of TRAIL‐induced apoptosis in patients with OS. [ABSTRACT FROM AUTHOR]

The tumour necrosis factor superfamily (TNFSF) plays critical roles in tumour apoptosis, tissue morphogenesis and lineage determination. TNFSF10 (TRAIL or Apol‐2) belongs to the tumour necrosis factor (TNF) cytokine family and induces rapid apoptosis in a wide variety of tumour cell lines upon binding to death‐inducing signalling receptors. In this study, we identified TNFSF10 from Nile tilapia (Oreochromis niloticus) and found it was most closely related to Japanese pufferfish (Takifugu rubripes) TNFSF10. Amino acid identity between tilapia TNFSF10 and mandarin fish (Siniperca chuatsi) TRAIL was 69.2%. The highest expression of TNFSF10 mRNA was observed in the liver. In vitro studies showed that the mRNA expression of TNFSF10 was significantly stimulated by LPS in head kidney leucocytes, but remarkably inhibited by Poly I:C in spleen leucocytes. In vivo studies showed Streptococcus agalactiae infection significantly induced the mRNA expression of TNFSF10 in both the head kidney and spleen. The soluble recombinant protein Trx‐TNFSF10 could induce cytotoxicity and apoptosis in HeLa cells with cycloheximide as a promoter. Taken together, these results in this study indicate that TNFSF10 may play important roles in the immune system of Nile tilapia. [ABSTRACT FROM AUTHOR]

Regulation of neuroinflammation and β‐amyloid (Aβ) production are critical factors in the pathogenesis of Alzheimer's disease (AD). Cathepsin E (CatE), an aspartic protease, is widely studied as an inducer of growth arrest and apoptosis in several types of cancer cells. However, the function of CatE in AD is unknown. In this study, we demonstrated that the ablation of CatE in human amyloid precursor protein knock‐in mice, called APPNL−G−F mice, significantly reduced Aβ accumulation, neuroinflammation, and cognitive impairments. Mechanistically, microglial CatE is involved in the secretion of soluble TNF‐related apoptosis‐inducing ligand, which plays an important role in microglia‐mediated NF‐κB‐dependent neuroinflammation and neuronal Aβ production by beta‐site APP cleaving enzyme 1. Furthermore, cannula‐delivered CatE inhibitors improved memory function and reduced Aβ accumulation and neuroinflammation in AD mice. Our findings reveal that CatE as a modulator of microglial activation and neurodegeneration in AD and suggest CatE as a therapeutic target for AD by targeting neuroinflammation and Aβ pathology. [ABSTRACT FROM AUTHOR]

Escaping apoptosis is a hallmark of cancer. Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL), a central molecule that regulates the extrinsic apoptotic pathway, has been widely investigated in human oncology; however, investigations focusing on the endogenous expression of TRAIL in canine tumours are lacking. Therefore, we aimed to examine the expression of endogenous TRAIL in canine mammary tumours and analysed its correlation with downstream molecules Fas‐associated protein with death domain (FADD) and caspase‐3, and to the apoptotic index. A total of 147 samples, classified as normal mammary gland (n = 9), mammary adenoma (n = 30), low‐grade carcinoma (n = 42) and high‐grade carcinoma (n = 66), were included in the immunohistochemical analyses, and 43 samples with sufficient levels of RNA were analysed via RNA in situ hybridization and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. In immunohistochemistry, TRAIL protein expression was significantly decreased in high‐grade carcinoma compared to those in normal mammary gland and adenoma, with similar downregulation of TRAIL mRNA expression. Also, FADD and caspase‐3 expression positively correlated with TRAIL expression. However, the apoptotic index was paradoxically elevated in high‐grade tumours. Overall, these results suggest that the loss of TRAIL accompanied by dysregulation of TRAIL‐induced extrinsic apoptotic pathway molecules could affect malignant progression of canine mammary tumours. [ABSTRACT FROM AUTHOR]

Cancer cell therapy using cytotoxic T lymphocytes (CTL) or mesenchymal stem cells (MSC) possesses hurdles due to the cells, susceptibility to host induced changes. Here, versatile inanimate broadly applicable nanovesicles, termed immunotherapeutic‐nano‐ghosts (iNGs), are armed with inherent surface‐associated targeting and therapeutic capabilities in which the promise and benefits of MSC therapy and T cell immunotherapy are combined into one powerful off‐the‐shelf approach for treating malignant diseases. To mimic the cytotoxic or immunosuppressive functions of T cells, iNG are produced from MSC that were genetically engineered (GE) or metabolically manipulated to express additional membrane‐bound proteins, endowing the NGs derived therefrom with additional surface‐associated functions such as tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL). iNGs from GE‐MSCs (GE‐iNGs) show superior TRAIL retention and induce apoptosis in different cancer cell lines in vitro. In vivo studies on a human melanoma model demonstrate that a systemic, three‐day frequency, administration of GE‐iNGs result in tumor inhibition comparable to a six orders of magnitude higher concentration of soluble TRAIL. The iNGs are therefore a promising nanovesicle platform that can affect tumors in a non‐immunogenic manner while avoiding the need for a highly effective therapeutic concentration. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death. Pyronaridine, a synthetic drug of artemisinin, has been used in China for over 30 years for the treatment of malaria, but its effect on non‐small cell lung cancer (NSCLC) cells is rarely reported. In this study, we determined the efficacy of pyronaridine in four different NSCLC cell lines and explored its mechanism in H1975. The data showed that pyronaridine could upregulate the expression of TNF‐related apoptosis‐inducing ligand (TRAIL)‐mediated death receptor 5 to promote cellular apoptosis. Meanwhile, the JNK (c‐Jun N‐terminal kinase) level was detected to be significantly increased after treating with pyronaridine. We used JNK inhibitor and found that it could partially inhibit cell apoptosis. The results showed that epidermal growth factor receptor (EGFR), PI3K, and AKT were downregulated after the treatment of pyronaridine. In summary, pyronaridine can selectively kill NSCLC by regulating TRAIL‐mediated apoptosis and downregulating the protein level of EGFR. It is a promising anticancer drug for NSCLC. [ABSTRACT FROM AUTHOR]

Inhibition of CDK4/6 slows the cell cycle and induces senescence in breast cancer cells. However, senescent cancer cells promote invasion and metastasis. Several drugs reportedly target senescent cells, including ABT-263 (navitoclax). We examined the effects of the CDK4/6 inhibitor abemaciclib and ABT-263 on two human breast cancer cell lines. The abemaciclib and ABT-263 combination additively decreased the viability of MDA-MB-231 cells, but not MCF-7 cells. Also, the combination therapy-induced caspase-dependent apoptosis in MDA-MB-231 cells. Combination therapy with abemaciclib and ABT-737, an ABT-263 analog, significantly suppressed the in vivo growth of MDA-MB-231 with transient body-weight loss. Given that p16Ink4a and p21Cip1/Waf1 are key factors in senescence and that both cell lines were negative for p16, the role of p21 in apoptosis of treated breast cancer cells was investigated. Although abemaciclib increased the cytoplasmic p21 level in both cell lines as a hallmark of senescence, the abemaciclib and ABT-263 combination decreased it only in MDA-MB-231 cells. This decrease of p21 expression was relieved by caspase inhibition, and p21 was colocalized with caspase-3 in the cytoplasm of MDA-MB-231 cells. Alternatively, small interfering RNA-mediated knockdown of p21 rendered caspase-3-negative MCF-7 cells susceptible to abemaciclib and ABT-263, as well as TNF-related apoptosis-inducing ligand. Furthermore, a clinical database analysis showed that p21high breast cancer patients had a poorer prognosis compared to p21low patients. These results suggest that cytoplasmic p21 plays a protective role in apoptosis of CDK4/6 inhibitor-induced senescent breast cancer cells.Cip1/Waf1. [ABSTRACT FROM AUTHOR]

Transient receptor potential cation channel subfamily M member 7 (TRPM7) composed of an ion channel and a kinase domain regulates triple‐negative breast cancer (TNBC) cell migration, invasion, and metastasis, but it does not modulate TNBC proliferation. However, previous studies have shown that the combination treatment of nonselective TRPM7 channel inhibitors (2‐aminoethoxydiphenyl borate and Gd3+) with tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) increases antiproliferative effects and apoptosis in prostate cancer cells and hepatic stellate cells. We, therefore, investigated the potential role of TRPM7 in proliferation and apoptosis of TNBC cells (MDA‐MB‐231 and MDA‐MB‐468 cells) with TRAIL. We demonstrated that suppression of TRPM7 via TRPM7 knockdown or pharmacological inhibition synergistically increases TRAIL‐induced antiproliferative effects and apoptosis in TNBC cells. Furthermore, we showed that the synergistic interaction might be associated with TRPM7 channel activities using combination treatments of TRAIL and TRPM7 inhibitors (NS8593 as a TRPM7 channel inhibitor and TG100‐115 as a TRPM7 kinase inhibitor). We reveal that downregulation of cellular FLICE‐inhibitory protein via inhibition of Ca2+ influx might be involved in the synergistic interaction. Our study would provide both a new role of TRPM7 in TNBC cell apoptosis and a potential combinatorial therapeutic strategy using TRPM7 inhibitors with TRAIL in the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Studies suggest that tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) has vasoprotective potential, as low levels of TRAIL cause accelerated vascular calcification, whereas exogenous TRAIL administration exhibits anti‐atherosclerotic activity. The mechanism of TRAIL‐mediated vasoprotection remains unclear. We studied the effects of TRAIL (100 ng/ml) on human aortic endothelial cells (HAECs) exposed to pro‐atherogenic conditions; (a) oscillatory shear stress (±10 dynes/cm2) using the ibidi µ‐slide fluidic system; (b) pro‐inflammatory injury, that is, tumor necrosis factor alpha (TNF‐α, 100 ng/ml) and hyperglycemia (30 mM d‐glucose). End‐points examined included inflammatory gene expression and reactive oxygen species (ROS) formation. TRAIL shifted the net gene expression toward an antioxidant phenotype in HAECs exposed to oscillatory shear stress. TRAIL significantly reduced ROS formation in HAECs exposed to both TNF‐α and hyperglycemia. Therefore, TRAIL appears to confer atheroprotective effects on the endothelium, at least in part, by reducing oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the ability of α-tocopheryl succinate (α-TOS) to sensitise TRAIL-resistant malignant mesothelioma (MM) cells to TRAIL-induced apoptosis. We show that α-TOS activates expression of DR4/DR5 in a p53-dependent manner and re-establishes sensitivity of resistant MM cells to TRAIL-mediated apoptosis, as documented in p53wt MM cells but not in their p53null counterparts. MM cells selected for TRAIL resistance expressed low cell surface levels of DR4 and DR5. Treatment with sub-lethal doses of α-TOS restored expression of DR4 and DR5. The ability of α-TOS to modulate expression of pro-apoptotic genes may play a role in sensitisation of tumour cells to immunological stimuli. [Copyright &y& Elsevier]