Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries |
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| Authors: | Xiaonan Zhang Mihir Shetty Valentino Clemente Stig Linder Martina Bazzaro |
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| Affiliation: | 1.Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden;2.Masonic Cancer Center and Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN 55455, USA; (M.S.); (V.C.);3.Department of Biomedical and Clinical Sciences (BKV), Linköping University, 58183 Linköping, Sweden;4.Department of Oncology and Pathology, Karolinska Institute, 17176 Stockholm, Sweden |
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| Abstract: | Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs. |
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| Keywords: | ARID1A OCCC mitochondria ovarian cancer |
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