期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 12, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI143691
关键词
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资金
- NIH [R01CA148828, R01CA245546, R01DK095201, R37CA237421, R01CA248160, R01CA244931, R01CA215607, DK097153]
- University of Michigan Comprehensive Cancer Center (UMCCC) [P30CA046592, R35GM130183]
- University of Michigan GI SPORE Molecular Pathology and Biosample Core [P50CA130810]
- Center for Gastrointestinal Research [DK034933]
- Department of Defense [CA171086]
- NIH/NCI T32 Training Grant in Cancer Biology [5T32CA009676-2 7]
- Charles Woodson Research Fund
- UM Pediatric Brain Tumor Initiative
This study reveals the essential role of HIF-2α in colorectal cancer (CRC) progression, demonstrating its regulation of cell death via modulation of cellular iron and oxidation. Inhibitors targeting HIF-2α can enhance cancer cells' susceptibility to oxidative cell death.
Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, and metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factors hypoxia-inducible factor 1 alpha (HIF-1 alpha) and HIF-2 alpha. Our work demonstrates that HIF-2 alpha is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2 alpha. To overcome this limitation, we performed a small molecule screen to identify HIF-2 alpha -dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2 alpha- expressing tumor enteroids. Our work demonstrated that HIF-2 alpha integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2 alpha upregulated lipid and iron regulatory genes in CRC cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Second, via an iron-dependent, lipid peroxidation-independent pathway, HIF-2 alpha activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2 alpha decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2 alpha that can be leveraged for CRC treatment.
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