TY - JOUR
T1 - Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion
AU - Kohno, Susumu
AU - Linn, Paing
AU - Nagatani, Naoko
AU - Watanabe, Yoshihiro
AU - Kumar, Sharad
AU - Soga, Tomoyoshi
AU - Takahashi, Chiaki
N1 - Funding Information:
Acknowledgements We thank Drs. Y. Hirota and S. Tsutsumi for the substantial contribution to the initiation of work, Dr. A. Mizokami for helpful discussion, and Dr. Y. Watanabe for suggestion on research direction. This study was supported by Funding Program for Next Generation World-Leading Researchers (LS049) from cabinet office of Japan, Grant-in-Aid for Scientific Research (17H03576, 17K19586 and 19K22555 to CT, and 17K14992 and 20K07612 to SK) from MEXT, Project for Cancer Research and Therapeutic (P-CREATE) (19cm0106164h0001) from Japan Agency for Medical Research and Development (AMED), and TaNeDS (C1010568) and a collaborative research fund (C1010818) from Daiichi-Sankyo Co. Ltd. SK was supported by a Senior Principal Research Fellowship from the National Health & Medical Research Council of Australia (GNT 1103006).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - RB1 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.
AB - RB1 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.
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U2 - 10.1038/s41388-020-1381-6
DO - 10.1038/s41388-020-1381-6
M3 - Article
C2 - 32694611
AN - SCOPUS:85088273846
SN - 0950-9232
VL - 39
SP - 5690
EP - 5707
JO - Oncogene
JF - Oncogene
IS - 34
ER -
