HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells
Open accessPublished version of a preprint
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. Cancer Res; 77(8); 2064–77. ©2017 AACR.
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Several transcription factors including AP-1, CREB, ATF4, and NRF2 have been shown to regulate either directly or indirectly GPX4 levels in different cellular contexts.
“Several transcription factors including AP-1 (60, 61), CREB (62, 63), ATF4 (64), and NRF2 (45, 65, 66) have been shown to regulate either directly or indirectly GPX4 levels in different cellular contexts.”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [64]
The ability of ATF4 to upregulate system xc− and stabilize GPX4 upon HSPA5 transactivation is causally involved in some models of oncogenesis and chemoresistance to ferroptosis induction.
“the ability of ATF4 to upregulate system xc− and stabilize GPX4 (upon HSPA5 transactivation) is causally involved in some models of oncogenesis and chemoresistance to ferroptosis induction [580, 599].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [580]
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References 44 · Cited by 576
- Authors
- Zhu, S., Zhang, Q., Sun, X., Zeh, H. J., Lotze, M. T., Kang, R., & Tang, D.
- Affiliations
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- University of Pittsburgh (US)
- Corresponding author
- Tang, Daolin
- Venue
- Cancer Research
- Published
- 2017-04-13
- Volume
- 77
- Issue
- 8
- Pages
- 2064-2077
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5392369
- OpenAlex
- W2582111083
- Cited by
- 576
- References
- 44
- Citations by year
- 2026: 53 · 2025: 79 · 2024: 77 · 2023: 90 · 2022: 107 · 2021: 85 · 2020: 38 · 2019: 20 · 2018: 18 · 2017: 9
- FWCI
- 19.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01CA160417, R01GM115366, and R01CA181450)
- Pancreatic Cancer Action Network (13-20-25-TANG)
- American Cancer Society (RSG-16-014-01-CDD)
- National Natural Science Foundation of China (31671435)
- National Natural Science Foundation of Guangdong (2016A030308)
- University of Pittsburgh Cancer Institute (P30CA047904)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- GRP78, ferroptosis, pancreatic ductal adenocarcinoma, ATF4, GPX4, lipid peroxidation, gemcitabine resistance, heat shock proteins, protein degradation, anticancer drug sensitivity
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Endoplasmic Reticulum Chaperone BiP, Gemcitabine, Animals, Antimetabolites, Antineoplastic, Deoxycytidine, Glutathione Peroxidase, Heat-Shock Proteins, Humans, Pancreatic Neoplasms, Lipid Peroxidation, Cell Death, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Activating Transcription Factor 4
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