The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells

Yuto Sekiguchi, Mayuka Yamada, Takuya Noguchi, Chise Noomote, Mei Tsuchida, Yuki Kudoh, Yusuke Hirata, Atsushi Matsuzawa

Research output: Contribution to journalLetterpeer-review

2 Citations (Scopus)

Abstract

Fas/CD95 plays a pivotal role in T cell-mediated cytotoxicity. Accumulating evidence has suggested that resistance to Fas-mediated apoptosis contributes to the escape of cancer cells from immune destruction, and allows to undergo proliferation and outgrowth of cancer cells. In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downregulated heat shock protein 70 (HSP70) as previously reported. Considering that HSP70 contributes to protection of cells against Fas-mediated apoptosis, gefitinib may increase the sensitivity to Fas-mediated apoptosis by downregulating HSP70. Thus, our findings reveal novel properties of gefitinib, which may provide insight into the alternative therapeutic approaches of gefitinib for Fas-resistant tumors.

Original languageEnglish
Pages (from-to)435-440
Number of pages6
JournalJournal of Toxicological Sciences
Volume44
Issue number6
DOIs
Publication statusPublished - 2019 Jan 1

Keywords

  • Apoptosis
  • Chemotherapeutic agent
  • Fas
  • Gefitinib
  • HSP70

ASJC Scopus subject areas

  • Toxicology

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