Abstract
Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor-initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of interleukin 6 (IL-6). We show that the iron dependence of ovarian cancer TICs renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.
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Acknowledgements
Supported in part by NIH grants R01 CA188025 (SVT), R01 CA171101 (FMT), the Department of Defense (W81XWH-10-1-0289 to CC), and Scholar grants from the Cancer Prevention and Research Institute of Texas (CPRIT; to WX and FM). We thank Tara L Arvedson (Amgen, Thousand Oaks, CA) for a generous gift of anti-ferroportin antibody.
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Basuli, D., Tesfay, L., Deng, Z. et al. Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene 36, 4089–4099 (2017). https://doi.org/10.1038/onc.2017.11
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DOI: https://doi.org/10.1038/onc.2017.11
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