| RRC ID |
79058
|
| 著者 |
Kohno S, Linn P, Nagatani N, Watanabe Y, Kumar S, Soga T, Takahashi C.
|
| タイトル |
Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion.
|
| ジャーナル |
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.
|
| 巻・号 |
39(34)
|
| ページ |
5690-5707
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
PC-3(RCB2145)
LNCap.FGC(RCB2144) |
