Open AccessEffect of AKT 3 expression on MYC ‐ and caspase‐8‐dependent apoptosis caused by polo‐like kinase inhibitors in HCT 116 cells
Author(s) -
omiya Yuma,
Noguchi Kohji,
Tanaka Noritaka,
Kasagaki Takahiro,
Katayama Kazuhiro,
Sugimoto Yoshikazu
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13093
Subject(s) - protein kinase b , polo like kinase , apoptosis , kinase , downregulation and upregulation , cancer research , caspase 3 , cell cycle , caspase , cell growth , biology , cell culture , microbiology and biotechnology , programmed cell death , biochemistry , genetics , gene
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 ( PLK is), including BI 2536, BI 6727, and GSK 461364, 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 PLK is. We showed that PLK i‐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 AKT 3 was upregulated, whereas that of MYC was downregulated in some BI 2536‐resistant cell lines. Expression of P‐ GP conferred resistance to PLK is, and PLK i‐induced apoptosis was dependent on MYC and caspase‐8 in HCT 116 cells. We also showed for the first time that AKT 3 suppressed BI 6727‐induced caspase‐8 activation and conferred resistance to PLK is. Collectively, these results indicate that MYC , caspase‐8, P‐ GP , and AKT 3 play critical roles in PLK i‐induced apoptosis. Therefore, they are candidate biomarkers of the pharmacological efficacy of PLK is.