HSPA5 regulates ferroptotic cell death in cancer cells

Shan Zhu, Qiuhong Zhang, Xiaofan Sun, Herbert J. Zeh, Michael T. Lotze, Rui Kang, Daolin Tang

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis in vitro and in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance.

Original languageEnglish (US)
Pages (from-to)2064-2077
Number of pages14
JournalCancer Research
Volume77
Issue number8
DOIs
StatePublished - Apr 15 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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