HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

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…

• AC
  American Cancer Society

  Award: RSG-16-014-01-CDD
• PC
  Pancreatic Cancer Action Network

  Award: 13-20-25-TANG
• NN
  National Natural Science Foundation of China

  Award: 31671435
• NI
  National Institutes of Health

  Award: R01CA160417, R01GM115366, and R01CA181450
• CI
  Cancer Institute, University of Pittsburgh

  Award: P30CA047904