Susumu Kohno, Paing Linn, Naoko Nagatani, Yoshihiro Watanabe, Sharad Kumar, Tomoyoshi Soga, Chiaki Takahashi
Oncogene 2020 AugRB1 gene is often homozygously deleted or mutated in prostate adenocarcinomas following acquirement of castration resistance and/or metastatic ability. We found that SUCLA2 gene is frequently involved in the deletion of the RB1 gene region in advanced prostate cancer. SUCLA2 constitutes the β-subunit of succinate CoA ligase heterodimer that reversibly converts succinyl CoA into succinate. We sought the possibility that deletion of SUCLA2 gives rise to a metabolic vulnerability that could be targeted therapeutically. We found a significant metabolic shift in SUCLA2-deleted prostate cancer cells, including lower mitochondrial respiratory activity. By screening a number of libraries for compounds that induce cell death selectively in SUCLA2-deficient prostate cancer cells, we identified thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) and PMA (phorbol-12-myristate-13-acetate) from a natural compound library. These findings indicate that the metabolic vulnerability in SUCLA2-deficient prostate cancer cells is pharmacologically targetable.
Susumu Kohno, Paing Linn, Naoko Nagatani, Yoshihiro Watanabe, Sharad Kumar, Tomoyoshi Soga, Chiaki Takahashi. Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion. Oncogene. 2020 Aug;39(34):5690-5707
PMID: 32694611
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