Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion

Oncogene
Susumu KohnoChiaki Takahashi

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.

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Citations

Dec 1, 2020·IScience·Thomas N SeyfriedChristos Chinopoulos
Aug 8, 2021·Cancers·Paing LinnChiaki Takahashi

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Methods Mentioned

BETA
FACS
flow cytometry
xenograft
xenografts
PMA
biopsy
PCR
Transfection
electrophoresis

Software Mentioned

GraphPad Prism8
PLS
RECLU
DNAFORM
GSEA
all
R
BWA
Metaboanalyst
QEA

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