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HSPB1 as a novel regulator of ferroptotic cancer cell death

Oncogene volume 34, pages 5617–5625 (2015)Cite this article

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Abstract

Ferroptosis is an iron-dependent form of non-apoptotic cell death, but its molecular mechanism remains largely unknown. Here, we demonstrate that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptotic cancer cell death. Erastin, a specific ferroptosis-inducing compound, stimulates heat shock factor 1 (HSF1)-dependent HSPB1 expression in cancer cells. Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. Protein kinase C-mediated HSPB1 phosphorylation confers protection against ferroptosis by reducing iron-mediated production of lipid reactive oxygen species. Moreover, inhibition of the HSF1–HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity of erastin in human xenograft mouse tumor models. Our findings reveal an essential role for HSPB1 in iron metabolism with important effects on ferroptosis-mediated cancer therapy.

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Acknowledgements

We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by the National Institutes of Health (R01CA160417 to DT), a 2013 Pancreatic Cancer Action Network-AACR Career Development Award (Grant Number 13-20-25-TANG), The National Natural Science Foundation-Guangdong Joint Fund (U1132005 to XS) and Science and Information Technology of Guangzhou Key Project (2011Y1-00038 to XS). HW is supported by grants from the National Center of Complementary and Alternative Medicine (R01AT005076) and the National Institute of General Medical Sciences (R01GM063075).

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Authors and Affiliations

  1. Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    X Sun, Z Ou, Y Fan, X Niu & D Tang

  2. Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    X Sun, Z Ou, Y Fan, X Niu & D Tang

  3. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China

    M Xie & L Cao

  4. Department of Surgery, University of Pittsburgh Cancer Institute,

    R Kang & D Tang

  5. University of Pittsburgh, Pittsburgh, PA, USA

    R Kang & D Tang

  6. Department of Emergency Medicine, North Shore University Hospital, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    H Wang

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Sun, X., Ou, Z., Xie, M. et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 34, 5617–5625 (2015). https://doi.org/10.1038/onc.2015.32

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