Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells.
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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DOI：
10.1111/cas.13093
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发表时间：
2016-12
期刊：
影响因子：
5.7
通讯作者：
Sugimoto Y
中科院分区：
文献类型：
--
作者：
Nonomiya Y;Noguchi K;Tanaka N;Kasagaki T;Katayama K;Sugimoto Y
Polo样激酶（PLK）是一种细胞周期调节因子，在多种癌细胞类型中过表达。Polo样激酶被认为是癌症治疗的新靶点，包括BI 2536、BI 6727和GSK461364在内的几种PLK抑制剂（PLKis）已经被开发出来。在这项研究中，我们从人类结直肠癌HCT 116细胞中建立了5个BI 2536耐药细胞系，以探索耐药机制并鉴定可预测的PLKis生物标志物。我们发现PLKi诱导的caspase - 8激活在BI 2536抗性细胞系中减弱。我们还发现，在一些BI 2536抗性细胞系中，P糖蛋白（P‐GP）和AKT3的表达上调，而MYC的表达下调。在HCT 116细胞中，P‐GP的表达赋予了对PLKis的抗性，PLKi诱导的细胞凋亡依赖于MYC和caspase‐8。我们还首次发现，AKT3抑制了BI 6727诱导的caspase - 8激活，并赋予了对PLKis的抗性。总之，这些结果表明MYC、caspase‐8、P‐GP和AKT3在PLKi‐诱导的细胞凋亡中起关键作用。因此，它们是PLKis药理功效的候选生物标志物。
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.
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