Inhibition of checkpoint kinase 1 abrogates G2/M checkpoint activation and promotes apoptosis under heat stress

Yukihiro Furusawa, Takashi Iizumi, Yoshisada Fujiwara, Qing Li Zhao, Yoshiaki Tabuchi, Takaharu Nomura, Takashi Kondo

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Hyperthermia induced by heat stress (HS) inhibits the proliferation of cancer cells and induces their apoptosis. However, the mechanism underlying HS-induced apoptosis remains elusive. Here, we demonstrated a novel evidence that checkpoint kinase 1 (Chk1) plays crucial roles in the apoptosis and regulation of cell cycle progression in cells under HS. In human leukemia Jurkat cells, interestingly, the ataxia telangiectasia and Rad-3 related (ATR)-Chk1 pathway was preferentially activated rather than the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) pathway under HS. The selective inhibitors of ATR or Chk1 abrogated HSinduced apoptosis in human leukemia Jurkat cells whereas the inhibition of ATM or Chk2 caused only marginal effects. Inhibition of ATR and Chk1 also abrogated G2/M checkpoint activation by HS in Jurkat cells. The effects of small interfering RNA targeting Chk1 were similar to those of the selective inhibitor of Chk1. In addition, the efficiencies of Chk1 inhibition on G2/M checkpoint abrogation and apoptosis induction were confirmed in the adherent cancer cell lines HeLa, HSC3, and PC3, suggesting that the targeting of Chk1 can be effective in solid tumors cells. In conclusion, these findings indicate a novel molecular basis of G2/M checkpoint activation and apoptosis in cells exposed to HS.

Original languageEnglish
Pages (from-to)102-112
Number of pages11
JournalApoptosis
Volume17
Issue number1
DOIs
Publication statusPublished - 2012 Jan 1

Keywords

  • ATR
  • Cell cycle
  • Chk1
  • DNA damage response
  • Heat stress
  • Hyperthermia

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

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  • Cite this

    Furusawa, Y., Iizumi, T., Fujiwara, Y., Zhao, Q. L., Tabuchi, Y., Nomura, T., & Kondo, T. (2012). Inhibition of checkpoint kinase 1 abrogates G2/M checkpoint activation and promotes apoptosis under heat stress. Apoptosis, 17(1), 102-112. https://doi.org/10.1007/s10495-011-0660-7