RRC ID 79058
Author Kohno S, Linn P, Nagatani N, Watanabe Y, Kumar S, Soga T, Takahashi C.
Title Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion.
Journal Oncogene
Abstract 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.
Volume 39(34)
Pages 5690-5707
Published 2020-8-1
DOI 10.1038/s41388-020-1381-6
PII 10.1038/s41388-020-1381-6
PMID 32694611
MeSH Animals Apoptosis / drug effects Apoptosis / genetics Benzoquinones / pharmacology Cell Line, Tumor Gene Deletion* HEK293 Cells Humans Male Mice, Knockout Mice, Nude Mice, SCID PC-3 Cells Prostatic Neoplasms / genetics* Prostatic Neoplasms / metabolism Prostatic Neoplasms / pathology Retinoblastoma Protein / deficiency Retinoblastoma Protein / genetics* Succinate-CoA Ligases / deficiency Succinate-CoA Ligases / genetics* Tetradecanoylphorbol Acetate / analogs & derivatives Tetradecanoylphorbol Acetate / pharmacology
Human and Animal Cells PC-3(RCB2145) LNCap.FGC(RCB2144)