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

Yuma Nonomiya, Kohji Noguchi, Noritaka Tanaka, Takahiro Kasagaki, Kazuhiro Katayama, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1877-1887
Number of pages11
JournalCancer Science
Volume107
Issue number12
DOIs
Publication statusPublished - 2016 Dec 1

Fingerprint

HCT116 Cells
Caspase 8
P-Glycoprotein
Phosphotransferases
Apoptosis
Cell Line
Pharmacological Biomarkers
Colorectal Neoplasms
Neoplasms
Cell Cycle
Down-Regulation
Biomarkers
BI 2536
BI 6727

Keywords

  • AKT3
  • apoptosis
  • drug resistance
  • inhibitor
  • kinase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells. / Nonomiya, Yuma; Noguchi, Kohji; Tanaka, Noritaka; Kasagaki, Takahiro; Katayama, Kazuhiro; Sugimoto, Yoshikazu.

In: Cancer Science, Vol. 107, No. 12, 01.12.2016, p. 1877-1887.

Research output: Contribution to journalArticle

Nonomiya, Yuma ; Noguchi, Kohji ; Tanaka, Noritaka ; Kasagaki, Takahiro ; Katayama, Kazuhiro ; Sugimoto, Yoshikazu. / Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells. In: Cancer Science. 2016 ; Vol. 107, No. 12. pp. 1877-1887.
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