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Abstract: Objectives: Capillarisin (Cap), an active component of Artemisia capillaris root extracts, is characterized by its anti‐inflammatory, anti‐oxidant and anti‐cancer properties. Nevertheless, the functions of Cap in prostate cancer have not been fully explored. We evaluated the potential actions of Cap on the cell proliferation, migration and invasion of prostate carcinoma cells. Materials and methods: Cell proliferation and cell cycle distribution were measured by water‐soluble tetrazolium‐1 and flow cytometry assays. The expression of cyclins, p21, p27, survivin, matrix metallopeptidase (MMP2 and MMP9) were assessed by immunoblotting assays. Effects of Cap on invasion and migration were determined by wound closure and matrigel transmigration assays. The constitutive and interlukin‐6 (IL‐6)‐inducible STAT3 activation of prostate carcinoma cells were determined by immunoblotting and reporter assays. Results: Capillarisin inhibited androgen‐independent DU145 and androgen‐dependent LNCaP cell growth through the induction of cell cycle arrest at the G0/G1 phase by upregulating p21 and p27 while downregulating expression of cyclin D1, cyclin A and cyclin B. Cap decreased protein expression of survivin, MMP‐2, and MMP‐9 and therefore blocked the migration and invasion of DU145 cells. Cap suppressed constitutive and IL‐6‐inducible STAT3 activation in DU145 and LNCaP cells. Conclusions: Our data indicate that Cap blocked cell growth by modulation of p21, p27 and cyclins. The inhibitory effects of Cap on survivin, MMP‐2, MMP‐9 and STAT3 activation may account for the suppression of invasion in prostate carcinoma cells. Our data suggest that Cap might be a therapeutic agent in treating advanced prostate cancer with constitutive STAT3 or IL‐6‐inducible STAT3 activation. [ABSTRACT FROM AUTHOR]

ABSTRACT Glucose can activate the carbohydrate response element binding protein (ChREBP) transcription factor to control gene expressions in the metabolic pathways. The way of ChREBP involvement in human prostate cancer development remains undetermined. This study examined the interactions between prostate fibroblasts and cancer cells under the influences of ChREBP. Results showed that high glucose (30 mM) increased the phosphorylation of AKT at S473 and AMP‐activated protein kinase (AMPK) at S485 in human prostate fibroblast (HPrF) cells and prostate cancer PC‐3 cells. High glucose enhanced the expression of ChREBP, which increased the expressions of fibronectin, alpha‐smooth muscle actin (α‐SMA), and WNT1 inducible signaling pathway protein 1 (WISP1), magnifying the cell growth and contraction in HPrF cells in vitro. The cell proliferation, invasion, and tumor growth in prostate cancer PC‐3 cells were enhanced by inducing the expressions of ChREBP, mucosa‐associated lymphoid tissue 1 (MALT1), and epithelial‐mesenchymal transition markers with high glucose treatment. Moreover, ectopic ChREBP overexpression induced NF‐κB signaling activities via upregulating MALT1 expression in PC‐3 cells. Our findings illustrated that ChREBP is an oncogene in the human prostate. High glucose condition induces a glucose/ChREBP/MALT1/NF‐κB axis which links the glucose metabolism to the NF‐κB activation in prostate cancer cells, and a glucose/ChREBP/WISP1 axis mediating autocrine and paracrine signaling between fibroblasts and cancer cells to promote cell migration, contraction, growth, and invasion of the human prostate. [ABSTRACT FROM AUTHOR]

Maspin is a member of the clade B serine protease inhibitor superfamily and exhibits diverse regulatory effects in various types of solid tumors. We compared the expressions of maspin and determined its potential biological functions and regulatory mechanisms in bladder carcinoma cells in vitro and in vivo. The results of RT-qPCR indicated that maspin expressed significantly lower levels in the bladder cancer tissues than in the paired normal tissues. The immunohistochemical assays of human bladder tissue arrays revealed similar results. Maspin-knockdown enhanced cell invasion whereas the overexpression of maspin resulted in the opposite process taking place. Knockdown of maspin also enhanced tumorigenesis in vivo and downregulated protein levels of acetyl-histone H3. Moreover, in bladder carcinoma cells, maspin modulated HDAC1 target genes, including cyclin D1, p21, MMP9, and vimentin. Treatment with MK2206, which is an Akt inhibitor, upregulated maspin expression, whereas PTEN-knockdown or PTEN activity inhibitor (VO-OHpic) treatments demonstrated reverse results. The ectopic overexpression of p53 or camptothecin treatment induced maspin expression. Our study indicated that maspin is a PTEN-upregulated and p53-upregulated gene that blocks cell growth in vitro and in vivo, and may act as an HDAC1 inhibitor in bladder carcinoma cells. We consider that maspin is a potential tumor suppressor gene in bladder cancer. [ABSTRACT FROM AUTHOR]

Transgelin (TAGLN/SM22-α) is a regulator of the actin cytoskeleton, affecting the survival, migration, and apoptosis of various cancer cells divergently; however, the roles of TAGLN in bladder carcinoma cells remain inconclusive. We compared expressions of TAGLN in human bladder carcinoma cells to the normal human bladder tissues to determine the potential biological functions and regulatory mechanisms of TAGLN in bladder carcinoma cells. Results of RT-qPCR and immunoblot assays indicated that TAGLN expressions were higher in bladder smooth muscle cells, fibroblast cells, and normal epithelial cells than in carcinoma cells (RT-4, HT1376, TSGH-8301, and T24) in vitro. Besides, the results of RT-qPCR revealed that TAGLN expressions were higher in normal tissues than the paired tumor tissues. In vitro, TAGLN knockdown enhanced cell proliferation and invasion, while overexpression of TAGLN had the inverse effects in bladder carcinoma cells. Meanwhile, ectopic overexpression of TAGLN attenuated tumorigenesis in vivo. Immunofluorescence and immunoblot assays showed that TAGLN was predominantly in the cytosol and colocalized with F-actin. Ectopic overexpression of either p53 or PTEN induced TAGLN expression, while p53 knockdown downregulated TAGLN expression in bladder carcinoma cells. Our results indicate that TAGLN is a p53 and PTEN-upregulated gene, expressing higher levels in normal bladder epithelial cells than carcinoma cells. Further, TAGLN inhibited cell proliferation and invasion in vitro and blocked tumorigenesis in vivo. Collectively, it can be concluded that TAGLN is an antitumor gene in the human bladder. [ABSTRACT FROM AUTHOR]

Migration and invasion enhancer 1 (MIEN1) is a membrane-anchored protein and exists in various cancerous tissues. However, the roles of MIEN1 in prostate cancer have not yet been clearly addressed. We determined the expression, biological functions, and regulatory mechanisms of MIEN1 in the prostate. The results of immunohistochemical analysis indicated that MIEN1 was expressed specifically in epithelial cells and significantly higher in adenocarcinoma as compared to in normal tissues. MIEN1 enhanced in vitro cell proliferation, invasion, and in vivo tumorigenesis. Meanwhile, MIEN1 attenuated cisplatin-induced apoptosis in PC-3 cells. Overexpression of NF-ĸB-inducing kinase (NIK) enhanced MIEN1 expression, while overexpression of NF-ĸB inhibitor α (IĸBα) blocked MIEN1 expression in PC-3 cells. In prostate carcinoma cells, MIEN1 provoked Akt phosphorylation; moreover, MIEN1 downregulated N-myc downstream regulated 1 (NDRG1) but upregulated interleukin-6 (IL-6) gene expression. MK2206, an Akt inhibitor, impeded the modulation of MIEN1 on NDRG1 and IL-6 expressions. Our studies suggest that MIEN1 is an NF-ĸB downstream oncogene in the human prostate. Accordingly, the modulation of Akt signaling in the gene expressions of NDRG1 and IL-6 may account for the functions of MIEN1 in cell proliferation, invasion, and tumorigenesis in prostate carcinoma cells. [ABSTRACT FROM AUTHOR]

Hyperglycemia and hyperglycosuria, two primary characteristics of diabetes mellitus, may increase the risk of cancer initiation, particularly for bladder cancer. The effectiveness of metformin, a common antidiabetic agent, is determined by its ability to induce growth differentiation factor 15 (GDF15). However, the mechanism of the GDF15 in relation to glucose, which influences the tumor microenvironment in the human bladder, is not fully understood. This study explores the potential roles of GDF15 in response to glucose in the human bladder. High glucose treatment (30 mM) enhanced phosphorylation of AKT at S473 and AMP-activated protein kinase α1/2 (AMPKα1/2) at S485 to block the counteracting effect of metformin on the AMPK activity in bladder cancer and stroma [human bladder stromal fibroblast (HBdSF) and human bladder smooth muscle cell (HBdSMC)] cells compared with normal glucose treatment (5 mM). Metformin modulated the expressions of GDF15, NDRG1, Maspin, and epithelial-to-mesenchymal transition (EMT) markers to attenuate cell proliferation and invasion of bladder cancer cells. Caffeic acid phenethyl ester (CAPE), like metformin, behaves as an inducer of AMPK activity to stimulate GDF15 expression. Knockdown of GDF15 blocked the downregulation of CAPE on the contraction of HBdSMCs. Both CAPE-induced GDF15 expression and the supernatant from bladder cancer cells with overexpressing GDF15 impeded the HBdSF and HBdSMC migration, suggesting that CAPE-upregulated GDF15 blocked the cell migration. These findings reveal that high glucose treatment inhibits the counteracting effects of either metformin or CAPE on the AMPK activity and GDF15 is downregulated by glucose and induced by metformin and CAPE in both stroma and cancer cells. Furthermore, GDF15 is an antitumor gene facilitating communication between stroma and cancer cells in the human bladder. NEW & NOTEWORTHY This study investigates the counteraction of either CAPE or metformin with the AMPK activity increasing GDF15 expression in human bladder cells. The findings are the first study to indicate the secretion of GDF15 from cancer and stroma cells via autocrine or paracrine mechanisms. Our study suggests that GDF15, an antitumor gene in the human bladder induced by AMPK inducers, acts as a communication link between stroma and cancer cells in the human bladder.

Cervical cancer, uterus cancer, and ovarian cancer are three common gynecological cancers. After diagnosis, the three therapeutic modalities available for treating gynecological cancers include surgery, chemotherapy, and radiotherapy. During the diagnostic and treatment periods, these patients usually suffer from physical and psychologic distresses, including menopausal symptoms, infertility, sexual dysfunction, incontinence, anxiety, depression, and relationship changes, among others. Support from family members and significant others has the potential to buffer the psychological distress perceived by patients with gynecological cancers. However, those patients who undergo invasive treatment modalities or have intimate issues such as brachytherapy, the need to use a vaginal dilator, and sexual dysfunction tend to conceal relevant information from their families or friends, which may increase self-perceived loneliness when facing the impacts of the disease and treatments. Healthcare providers may help alleviate patients' psychological stresses by providing psychological support in a timely manner, initiating discussions of intimate issues, and fulfilling patient needs for related information. In addition, healthcare providers may provide one-on-one counseling and individualized care information to increase patients' understanding of their health status. Furthermore, during the COVID-19 pandemic, patients may self-isolate to avoid becoming infected or to recuperate from a COVID-19 infection, causing social isolation or delays of cancer treatment. Healthcare providers may further place caring phone calls and provide treatment information to increase patients' social support and lessen their psychological distress.