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Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion
Susumu Kohno1, Paing Linn2, Naoko Nagatani2
1Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan. skohno@staff.kanazawa-u.ac.jp.
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.
Insights
Advanced prostate cancer cells with RB1 gene deletions often lose SUCLA2, creating a metabolic vulnerability. Researchers identified thymoquinone and PMA as compounds that selectively kill these cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate adenocarcinomas frequently acquire castration resistance and metastatic ability, often associated with RB1 gene deletion or mutation.
- The SUCLA2 gene is frequently deleted in conjunction with the RB1 gene region in advanced prostate cancer.
- SUCLA2 encodes a subunit of succinate CoA ligase, an enzyme critical for the reversible conversion of succinyl CoA to succinate.
Purpose of the Study:
- To investigate the metabolic consequences of SUCLA2 deletion in prostate cancer.
- To identify therapeutic strategies targeting SUCLA2-deficient prostate cancer cells.
Main Methods:
- Comparative analysis of gene deletion patterns in prostate cancer.
- Metabolic profiling of SUCLA2-deleted versus SUCLA2-proficient prostate cancer cells.
- Screening of compound libraries for selective cytotoxicity against SUCLA2-deficient cells.
Main Results:
- SUCLA2 deletion in prostate cancer cells leads to significant metabolic alterations, including reduced mitochondrial respiratory activity.
- Thymoquinone and phorbol-12-myristate-13-acetate (PMA) were identified as compounds selectively inducing cell death in SUCLA2-deficient prostate cancer cells.
- These findings highlight a specific metabolic vulnerability exploitable for therapeutic intervention.
Conclusions:
- The deletion of SUCLA2 in advanced prostate cancer creates a targetable metabolic vulnerability.
- Natural compounds like thymoquinone and PMA show promise for selectively treating SUCLA2-deficient prostate cancers.
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