Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis

Abstract Background: MiR-541 acts as a tumor suppressor in some cancers. However, the role of miR-541 in regulating the chemosensitivity to cancer cells is still unclear. The aim of this study is to explore the effect of miR-541 on chemoresistance of pancreatic cancer (PCa) cells to gemcitabine-induced apoptosis.Methods: Gemcitabine-resistant Panc-1 and Capan-2 PCa cell lines (Panc-1/R and Capan-2/R) were established through long term exposure to gemcitabine. Effect of miR-541 on changing the sensitivity of Panc-1/R and Capan-2/R to gemcitabine-induced cytotoxicity was evaluated by MTT assays. Regulation of miR-541 on HAX-1 was confirmed by bioinformatics, western blot analysis and luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) was measured by flow cytometry analysis.Results: Comparison with Panc-1 and Capan-2, downregulation of miR-541 was observed in Panc-1/R and Capan-2/R cells. Overexpression of miR-541 was found to increase the cytotoxicity of gemcitabine to Panc-1/R and Capan-2/R cells. However, transfection with HAX-1 plasmid can abolish the effect of miR-541 on gemcitabine-induced cytotoxicity against Panc-1/R and Capan-2/R.Conclusion: Downregulation of miR-541 is responsible for development of gemcitabine resistance in PCa. Overexpression of miR-541 may represent a potential strategy to reverse the chemoresistance of PCa.

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9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.777114 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrey Poloznikov ◽

Sergey Nikulin ◽

Larisa Bolotina ◽

Andrei Kachmazov ◽

Maria Raigorodskaya ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Small Molecule ◽

Standard Of Care ◽

Small Molecule Inhibitor ◽

Future Research ◽

Molecular Alterations ◽

Pancreatic Cancer Cells ◽

Molecule Inhibitor ◽

Gsk 3Β

Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.

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Anti-Apoptotic BCL-2 Family Protein MCL-1 Plays a Critical Role in Baicalein-Induced Apoptosis in Human Pancreatic Cancer Cells

Gastroenterology ◽

10.1016/s0016-5085(11)62838-2 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-684

Author(s):

Hiroki Takahashi ◽

Monica C. Chen ◽

Diane M. Harris ◽

Hung Pham ◽

Howard A. Reber ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Critical Role ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells ◽

Family Protein ◽

Induced Apoptosis

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Triptolide to induce cell death of pancreatic cancer cells via inhibition of 14-3-3γ expression.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.425 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 425-425

Author(s):

Wei Wang ◽

Jinbing Luo ◽

Yinghui Liang ◽

Yubin Chen ◽

Wenjie Lin

Keyword(s):

Pancreatic Cancer ◽

Western Blot ◽

Cancer Cells ◽

Caspase 8 ◽

Down Regulation ◽

Pancreatic Cancer Cells ◽

Growth Inhibitory ◽

Induced Apoptosis

425 Background: Pancreatic cancer is one of the malignant tumors which exhibit resistance to chemotherapy. Gemcitabine-based therapy is a standard for advanced pancreatic cancer though it brings severe side-effect and average median survival is only 6 months. Hence increasing interest has focused on new agent with targeted therapies. Here we investigated the growth-inhibitory and apoptotic effect of triptolide, a diterpenoid triepoxide, and the role of 14-3-3γ expression in the apoptotic pathway induced by triptolide in human pancreatic cancer cells (AsPC-1 and PANC-1). Methods: Cell proliferation was measured by SRB, apoptotic cells were assessed by flow cytometry for Annexin V/PI staining and western blot for cleaved caspase-8, 9, 3 and fluorescent substrate assay for activities of caspase-8, 9, 3. To explore further mechanism of triptolide triggering death receptor pathway, specific siRNA targeted for 14-3-3γ was used to knock down 14-3-3γ expression measured by ELISA. In vivo, AsPC-1 xenografts in the absence or presence of stable down-regulation of 14-3-3γ expression by RNAi were treated with triptolide for 4 weeks and the tumor growth was compared, tumor samples were tested by ELISA and western blot for 14-3-3γ level. Results: Triptolide inhibits the proliferation at extremely low concentrations (12.5-50 nM) and induces apoptosis of pancreatic cancer cells through activating the caspase cascade associated with Bid cleavage. Moreover triptolide inhibited 14-3-3γ expression at dose and time-dependent manner and 14-3-3γ down-regulation sensitized cells to triptolide-induced apoptosis. Likewise, in vivo experiment of AsPC-1 xenografts, stable down-regulation of 14-3-3γ expression by RNAi significantly enhances triptolide-induced apoptosis and tumor growth delay. Conclusions: Triptolide exerted significant growth inhibitory effects and induced apoptosis in vitro and in vivo. Triptolide may have a potential to be an effective agent against pancreatic cancer and its mechanism of action is mediated by the inhibition of 14-3-3γ expression. The role of 14-3-3γ expression involved in resistance to apoptosis pathway make it be a potential therapeutic target in pancreatic cancer.

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