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Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells.

ABSTRACT: Polo-like kinase (PLK) is a cell-cycle regulator that is overexpressed in several cancer cell types. Polo-like kinase is considered a novel target for cancer therapies, and several PLK inhibitors (PLKis), including BI 2536, BI 6727, and GSK461364, have been developed. In this study, we established five BI 2536-resistant cell lines from human colorectal cancer HCT 116 cells, to explore the resistance mechanism and identify predictable biomarkers of PLKis. We showed that PLKi-induced caspase-8 activation was attenuated in the BI 2536-resistant cell lines. We also showed that the expression of P-glycoprotein (P-GP) and AKT3 was upregulated, whereas that of MYC was downregulated in some BI 2536-resistant cell lines. Expression of P-GP conferred resistance to PLKis, and PLKi-induced apoptosis was dependent on MYC and caspase-8 in HCT 116 cells. We also showed for the first time that AKT3 suppressed BI 6727-induced caspase-8 activation and conferred resistance to PLKis. Collectively, these results indicate that MYC, caspase-8, P-GP, and AKT3 play critical roles in PLKi-induced apoptosis. Therefore, they are candidate biomarkers of the pharmacological efficacy of PLKis.

SUBMITTER: Nonomiya Y

PROVIDER: S-EPMC5198950 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells.

Nonomiya Yuma Y Noguchi Kohji K Tanaka Noritaka N Kasagaki Takahiro T Katayama Kazuhiro K Sugimoto Yoshikazu Y

Cancer science 20161219 12

Polo-like kinase (PLK) is a cell-cycle regulator that is overexpressed in several cancer cell types. Polo-like kinase is considered a novel target for cancer therapies, and several PLK inhibitors (PLKis), including BI 2536, BI 6727, and GSK461364, have been developed. In this study, we established five BI 2536-resistant cell lines from human colorectal cancer HCT 116 cells, to explore the resistance mechanism and identify predictable biomarkers of PLKis. We showed that PLKi-induced caspase-8 act ...[more]

PMID: 27699933

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Project description:Curcumin is the main component of the Chinese herbal plant turmeric, which has been demonstrated to possess antitumor and other pharmacological properties. The aim of the present study was to investigate the effects of curcumin on the viability, migration and apoptosis of human colorectal carcinoma HCT?116 cells, and to explore the underlying molecular mechanisms. In addition, it was investigated whether the antitumor effect of curcumin on HCT?116 cells could match that of the chemotherapeutic drug 5?fluorouracil (5?FU). HCT?116 cells were treated with curcumin (10, 20 and 30 µM) and 5?FU (500 µM), and cell viability and proliferation were detected by Cell Counting Kit?8 and colony formation assays, respectively. The migration and invasion of treated cells were determined using Transwell and carboxyfluorescein succinimidyl amino ester fluorescent labeling assays. Cell cycle distribution and apoptosis rates were detected by flow cytometry. Furthermore, cell morphology changes associated with apoptosis were observed by fluorescence microscopy with acridine orange/ethidium bromide dual staining. To investigate the possible underlying molecular mechanisms, the gene and protein levels of Fas, Fas?associated via death domain (FADD), caspase?8, caspase?3, matrix metalloproteinase (MMP)?9, nuclear factor (NF)??B, E?cadherin and claudin?3 were detected using quantitative PCR analysis, zymography and western blotting. The results revealed that curcumin markedly inhibited the viability and proliferation of HCT?116 cells in a dose? and time?dependent manner. The migration, aggregation and invasion of HCT?116 cells into the lungs of mice were decreased by curcumin treatment in a dose?dependent manner. S?phase arrest and gradually increased apoptotic rates of HCT?116 cells were observed with increasing curcumin concentrations. Additionally, the mRNA and protein levels of apoptosis?associated proteins (Fas, FADD, caspase?8 and caspase?3) and E?cadherin in HCT?116 cells were upregulated following treatment with curcumin in a dose?dependent manner. By contrast, the expression of migration?associated proteins, including MMP?9, NF??B and claudin?3, was downregulated with increasing curcumin concentrations. These data suggested that the inhibitory effect of curcumin on HCT?116 cells may match that of 5?FU. Therefore, curcumin induced cell apoptosis and inhibited tumor cell metastasis by regulating the NF??B signaling pathway, and its therapeutic effect may be comparable to that of 5?FU.

Dataset Information

Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells.

Publications

Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells.

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