Iron addiction: a novel therapeutic target in ovarian cancer.
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.
Department of Molecular Biology and Biophysics,, University of Connecticut Health Center, Farmington, CT, USA.
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Basuli
Department of Molecular Biology and Biophysics,, University of Connecticut Health Center, Farmington, CT, USA.
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Tesfay
Department of Molecular Biology and Biophysics,, University of Connecticut Health Center, Farmington, CT, USA.
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Deng
Department of Molecular Biology and Biophysics,, University of Connecticut Health Center, Farmington, CT, USA.
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Paul
National Cancer Center Research Institute, Tokyo, Japan.
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Yamamoto
Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
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Ning
Center for Stem Cells and Regenerative Medicine, University of Texas Health Center, Houston, TX, USA.
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Xian
Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
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McKeon
Center for Quantitative Medicine, University of Connecticut Health Center, Farmington, CT, USA.
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Lynch
Department of Pathology, Brigham and Women's Hospital, Boston MA, USA.
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Crum
Department of Pathology,, University of Connecticut Health Center, Farmington, CT, USA.
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Hegde
Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, CT, USA.
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Brewer
Department of Pathology,, University of Connecticut Health Center, Farmington, CT, USA.
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Wang
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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Miller
Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT, USA.
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Dyment
Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA.
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Torti
Department of Molecular Biology and Biophysics,, University of Connecticut Health Center, Farmington, CT, USA.
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Torti
D000818:Animals; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
D007501:Iron