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Cryptotanshinone inhibits proliferation yet induces apoptosis by suppressing STAT3 signals in renal cell carcinoma.

ABSTRACT: It has been established that signal transducer and activator of transcription 3 serves as an oncoprotein in various human cancers; targeting it is therefore a reasonable approach for emerging cancer therapies. Cryptotanshinone, a natural compound extracted from the root of Salvia miltiorrhiza Bunge, has been identified as a potential STAT3 inhibitor. However, its functional role in renal cell carcinomas remains largely unknown. Therefore, we investigated the mode of action for cryptotanshinone. We found that cryptotanshinone substantially suppressed cancer cell growth while it promoted cell apoptosis by inhibiting the phosphorylation of STAT3 at Tyr705 and its blocking nuclear translocation. Coordinately, P-AKT, CyclinD1, C-MYC, MEKK2, and HGF were down-regulated and cell cycle progression was arrested at the G0/G1 phase, thereby attenuating cell proliferation. Moreover, the level of Cleaved-Caspase-3 was elevated while Bcl-2 and Survivin were down-regulated, accounting for the increased apoptosis. Furthermore, in vivo results revealed that cryptotanshinone effectively inhibits tumorigenesis in an A498-xenografted mouse model. Taken together, our data gives a more comprehensive understanding of how cryptotanshinone functions in renal cell carcinomas and demonstrates its potential as a powerful therapeutic approach to treat renal cell carcinomas.

SUBMITTER: Chen Z

PROVIDER: S-EPMC5564825 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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STK39 blockage by RNA interference inhibits the proliferation and induces the apoptosis of renal cell carcinoma.

Project description:AimRenal cell carcinoma (RCC), the most frequent type of primary renal malignancies, has a high mortality rate. Serine/threonine kinase 39 (STK39) is associated with various human diseases, including cancers. The current study aimed to investigate the functions of STK39 in RCC.Materials and methodsSTK39 expression levels in RCC and paired normal renal tissue samples were detected by real-time polymerase chain reaction and Western blotting analyses. The biological functions of STK39 were explored in two RCC cell lines with STK39 silence.ResultsSTK39 expression was significantly increased in RCC tissues than in normal renal tissues. Suppression of STK39 expression in ACHN and 786-0 cells significantly suppressed cell proliferation and induced cell apoptosis. Consistently, the expression of PCNA and Bcl-2 was remarkably increased, while the expression of Bax was significantly in STK39 knockdown cells compared to control cells. Furthermore, gene set enrichment analysis identified STK39 as an important regulator of p53 and p38 signaling pathways. STK39 knockdown increased p53 expression and inhibited p38 phosphorylation. Moreover, ectopic expression of STK39 in ACHN cells resulted in a reduced p53 expression and increased c-Myc and p-p38 expression. Such effects were suppressed by p38 inhibitor (SB203580).ConclusionSTK39 may exert its oncogenic function in RCC through p38 signaling. Our data suggest that STK39 may represent a potential therapeutic target against RCC.

| S-EPMC5860137 | biostudies-literature

Cucurbitacin E inhibits cellular proliferation and induces apoptosis in melanoma by suppressing HSDL2 expression.

Project description:BackgroundMelanoma is among the most aggressive types of skin malignancy and can have an unpredictable clinical course. Exploration of novel therapeutic targets and their regulators remains essential for the prevention and treatment of melanoma.MethodsHSDL2 protein levels were examined by immunohistochemistry. The roles of HSDL2 in cell proliferation and apoptosis were identified by CCK-8 and colony formation assays. The function of HSDL2 in cell apoptosis was analysed by flow cytometry. Western blotting, cell proliferation and apoptosis and a xenograft tumour model were utilized to explore the inhibitory functions and mechanisms of CuE in melanoma.ResultsHSDL2 is overexpressed in melanoma and promotes melanoma progression by activating the ERK and AKT pathways. CuE could inhibit the ERK and AKT pathways by decreasing HSDL2 expression; therefore, CuE could inhibit melanoma growth in vitro and in vivo.ConclusionHSDL2 may be a promising therapeutic target against melanoma, and CuE can inhibit melanoma by downregulating HSDL2 expression.

| S-EPMC8862504 | biostudies-literature

Solasonine Induces Apoptosis and Inhibits Proliferation of Bladder Cancer Cells by Suppressing NRP1 Expression.

Project description:Solasonine, a steroidal alkaloid extracted from Solanum nigrum L., has been found to exert inhibitory effect on cancers. However, the underlying anticancer mechanisms of solasonine, particularly in urinary bladder cancer (BC), remain unclear. In this study, we identified the potential targets and biological functions associated with solasonine activity using a bioinformatics approach. Ingenuity pathway analysis revealed that neuropilin-1 (NRP1) and other signaling pathways, such as PI3K/AKT and ERK/MAPK pathways, were potentially involved in the therapeutic effects of solasonine. The ability of solasonine in inducing apoptosis and inhibiting proliferation in BC cells was confirmed experimentally, and the inhibition of ERK/MAPK, P38/MAPK, and PI3K/AKT pathways was validated by Western blot. Mechanistically, solasonine suppressed the expression of NRP1 protein, but not that of mRNA. Further results of molecular docking and molecular dynamics simulation analysis indicated that solasonine could directly bind to the b1 domain of NRP1 protein with a reasonable and stable docking conformation. We previously found that targeting NRP1 is a potential antitumor strategy. Combined with these findings, it can be speculated that the binding of solasonine with NRP1 on the cell membrane could prevent the formation of NRP1/VEGFA/VEGFR2 and NRP1/EGFR complexes, resulting in the inhibition of downstream signaling, including ERK/MAPK, P38/MAPK, and PI3K/AKT pathways. Additionally, intracellular solasonine could inhibit the membrane localization of NRP1 and provoke its cytoplasmic retention, facilitating the degradation of NRP1 protein in the cytoplasm. The dual effects induced by the binding of solasonine to NRP1 extracellularly and intracellularly could account for the antiproliferative and proapoptotic effects of solasonine on BC.

| S-EPMC8906937 | biostudies-literature

Cryptotanshinone inhibits proliferation and induces apoptosis of breast cancer MCF-7 cells via GPER mediated PI3K/AKT signaling pathway.

Project description:G protein-coupled estrogen receptor (GPER) was reported to be a potential target in the breast cancer therapy. This study aimed to illuminate the function of GPER and its mediated PI3K/AKT pathway in cryptotanshinone (CPT) inducing cell apoptosis and antiproliferation effect on GPER positive breast cancer MCF-7 cells. Cell proliferation was tested by MTT assay. Apoptosis rates were tested by Annexin V-FITC/PI double staining and the cell cycle was researched by flow cytometry. Autodock vina was applied to make molecular docking between CPT or estradiol and GPER. siRNA technique and GPER specific agonist G-1 or antagonist G-15 were applied to verify the mediated function of GPER. Apoptosis and cell cycle related proteins, as well as the key proteins on PI3K/AKT signaling pathway were detected by western blot. The results indicated that CPT could exert antiproliferation effects by arresting cell cycle in G2/M phase and downregulating the expression of cyclin D, cyclin B and cyclin A. Besides, apoptosis induced by CPT was observed. CPT might be a novel GPER binding compounds. Significantly, suppression of PI3K/AKT signal transduction by CPT was further increased by G-1 and decreased by G-15. The study revealed that the effect of antiproliferation and apoptosis treating with CPT on MCF-7 cells might be through the downregulation of PI3K/AKT pathway mediated by activated GPER.

| S-EPMC8782479 | biostudies-literature

The natural polyphenol curcumin induces apoptosis by suppressing STAT3 signaling in esophageal squamous cell carcinoma.

Project description:BACKGROUND:We and others have previously shown that the STAT3 signaling pathway is activated in some esophageal squamous cell carcinoma (ESCC) cells and is required for the survival and growth of these primary ESCC-derived xenografts. It has also been shown that the natural polyphenol curcumin is an effective anti-tumor agent. METHODS:Luciferase assay and immunoblotting were performed to examine whether curcumin suppressed STAT3 signaling. CCK-8 assay and xenografts were utilized for analyzing ESCC cell growth in culture and mice. Soft agar assay was carried out to determine the colony formation ability of ESCC cells in the presence or absence of curcumin. Cell death and cell cycle were assessed by In CELL Analyzer 2000. Immunohistochemistry and TUNEL assay were used for detecting apoptosis in ESCC tisuses. Molecular docking was performed to evaluate the interaction of curcumin with JAK2. JAK2 activity was assessed using an in vitro cell-free system. HE staining was used to evaluate the ESCC tissues. RESULTS:The natural polyphenol curcumin inhibited STAT3 phosphorylation rapidly and blocked STAT3-mediated signaling in ESCC cells. It also induced growth arrest and apoptosis in cultured ESCC cells, which were attenuated by enforced expression of STAT3. Furthermore, curcumin preferentially blocked the growth of primary ESCC-derived xenografts that harbored activated STAT3. CONCLUSIONS:Curcumin is able to exert anti-tumor action through inhibiting the STAT3 signaling pathway. Giving its wide use in traditional medicines with low toxicity and few adverse reactions, it is conceivable that curcumin might be further explored as a unique STAT3 inhibitor for anti-cancer therapies.

| S-EPMC6280482 | biostudies-literature

DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis.

Project description:Hepatocellular carcinoma is one of the most common cancers in world wide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine [1-(β-ᴅ-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. Here, we demonstrated that zebularine exhibited antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis. Zebularine treatment down-regulated CDK2 and phosphorylation of retinoblastoma protein (RB), and up-regulated p21WAF/CIP1 and p53. We also found that zebularine treatment up-regulated phosphorylation of p44/42 MAPK. These results suggest that p44/42 MAPK pathway play a role in zebularine induced cell cycle arrest by regulating activity of p21WAF/CIP1 and Rb. Furthermore, we found that zebularine induced apoptosis. Although proapoptotic protein Bax levels were not affected, antiapoptotic protein Bcl-2 level was down-regulated with zebularine treatment. The data in the present study suggest that the action of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results provide a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma. Three each independent batches of zebuluarine-treated and control HepG2 cells were subjected to illumina Human methylation 450K Beadchip analysis.

2013-12-01 | E-GEOD-42490 | biostudies-arrayexpress

Proanthocyanidin B2 inhibits proliferation and induces apoptosis of osteosarcoma cells by suppressing the PI3K/AKT pathway.

Project description:Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. The long-term survival rate of OS patients is stubbornly low mainly due to the chemotherapy resistance. We therefore aimed to investigate the antitumoral effects and underlying mechanisms of proanthocyanidin B2 (PB2) on OS cells in the current study. The effect of PB2 on the proliferation and apoptosis of OS cell lines was assessed by CCK-8, colony formation, and flow cytometry assays. The target gene and protein expression levels were measured by qRT-PCR and Western blotting. A xenograft mouse model was established to assess the effects of PB2 on OS proliferation and apoptosis in vivo. Results from in vitro experiments showed that PB2 inhibited the proliferation and induced apoptosis of OS cells, and also increased the expression levels of apoptosis-related proteins. Moreover, PB2 induced OS cell apoptosis through suppressing the PI3K/AKT signalling pathway. The in vivo experiments further confirmed that PB2 could inhibit OS tumour growth and induce its apoptosis. Taken together, these results suggested that PB2 inhibited the proliferation and induced apoptosis of OS cells through the suppression of the PI3K/AKT signalling pathway.

| S-EPMC7579710 | biostudies-literature

S1PR1 promotes proliferation and inhibits apoptosis of esophageal squamous cell carcinoma through activating STAT3 pathway.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, which lacks effective biomarkers for prognosis. Therefore, it is urgent to explore new potential molecular markers to discriminate patients with poorer survival in ESCC.MethodsBioinformatics analysis, qRT-PCR, and western blot were applied to investigate S1PR1 expression. CCK-8 assay, colony formation assay, flow cytometry dual staining assay, and immunofluorescence were performed to examine cell proliferation ability and apoptosis rate. Mouse xenograft model of TE-13 cells was established to confirm the roles of S1PR1 in vivo. Gene set enrichment analysis (GSEA) was used to investigate the downstream signaling pathways related to S1PR1 functions. Co-IP was performed to verify the direct binding of S1PR1 and STAT3. Western blot was applied to determine the phosphorylation level of STAT3. Immunohistochemistry was conducted to identify protein expression of S1PR1 and p- STAT3 in tumor tissues.ResultsIn the present study, we found that S1PR1 expression was higher in ESCC patients and was a potential biomarker for poor prognosis. Silencing S1PR1 expression inhibited proliferation, and increased apoptosis of ESCC cells, while overexpression of S1PR1 had opposite effects. Mechanistically, S1PR1 played the roles of promoting proliferation and attenuating apoptosis through directly activating p-STAT3. Furthermore, in vivo experiments verified this mechanism.ConclusionOur findings indicated that S1PR1 enhanced proliferation and inhibited apoptosis of ESCC cells by activating STAT3 signaling pathway. S1PR1 may serve as a prognostic biomarker for clinical applications.

| S-EPMC6706905 | biostudies-literature

Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells.

Project description:The novel multitargeted tyrosine kinase inhibitor sunitinib is used as an antiangiogenic agent for the treatment of several types of cancer, including metastatic renal cell carcinoma (RCC). Sunitinib was shown to positively change the immunosuppressive phenotype in RCC patients. To improve its antitumor efficacy, and offer strategies for its combination with other approaches, it is critical to fully elucidate its mechanisms of action. We show that sunitinib induces tumor cell apoptosis and growth arrest in RCC tumor cells, which correlates with signal transducer and activator of transcription 3 (Stat3) activity inhibition. Sunitinib-mediated direct effects on tumor cells occur regardless of von Hippel-Lindau tumor suppressor gene status and hypoxia-inducible transcription factor-2alpha levels. Reduction of Stat3 activity enhances the antitumor effects of sunitinib, whereas expression of a constitutively activated Stat3 mutant rescues tumor cell death. Intravital multiphoton microscopy data show that sunitinib induces mouse Renca tumor cell apoptosis in vivo before tumor vasculature collapse. Sunitinib also inhibits Stat3 in Renca tumor-associated myeloid-derived suppressor cells (MDSC), down-regulates angiogenic gene expression, and reduces MDSCs and tumor T regulatory cells. These results suggest that Stat3 activity is important for RCC response to sunitinib, and Stat3 inhibition permits the direct proapoptotic activity of sunitinib on tumor cells and positive effects on tumor immunologic microenvironment.

| S-EPMC2664264 | biostudies-literature

Nodal induces apoptosis and inhibits proliferation in ovarian endometriosis-clear cell carcinoma lesions.

Project description:BackgroundExpression of Nodal, a member of the TGF-? superfamily, is commonly absent in differentiated tissues, while its re-expression occurs in a variety of human malignancy. However, little is known about its involvement in ovarian tumorigenesis. Herein, we focused on the functional roles of Nodal in ovarian endometriosis-carcinoma lesions.MethodsRegulation and function of Nodal and its associated molecules, including Smad2, GSK-3?, and several cell kinetics-related molecules, were assessed using clinical samples consisting of 108 ovarian carcinomas and 33 endometriotic lesions, as well as ES-2 (ovarian clear cell carcinoma; OCCCa) and Ishikawa (endometrial carcinoma) cell lines.ResultsNodal expression was significantly higher in endometriosis and OCCCa lesions as compared to that of non-OCCCas, with positive correlations to phosphorylated forms of both Smad2 (pSmad2) and GSK-3?. When compared to endometriotic lesions, the expression of Nodal and pSmad2 was significantly decreased in OCCCa. Treatment of Ishikawa cells with TGF-?1 resulted in transcriptional upregulation of Nodal, along with increased pSmad2 expression, while inhibition of GSK-3? also induced an increase in Nodal expression at the posttranslational level. Both ES-2 and Ishikawa cells stably overexpressing Nodal had increased susceptibility to apoptosis in response to treatment with cisplatin and doxorubicin, respectively, together with higher cleaved caspase-3 expression and decreased Bcl2/Bax ratio. Moreover, the stable Nodal-overexpressing cells showed reduced cell proliferation, along with increased expression of p27kip1 and p21waf1. In clinical samples, a significantly higher number of apoptotic cells and lower Ki-67 labeling indices were observed in Nodal-positive as compared to Nodal-negative OCCCa.ConclusionsThese findings suggest that Nodal is a multifunctional cytokine involved in the modulation of cell kinetics in ovarian endometriosis-OCCCa lesions.

| S-EPMC6448249 | biostudies-literature

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