Abstract | BACKGROUND: The development of castration-resistant prostate cancer (CRPC) remains a major obstacle in the treatment of prostate cancer (PCa). Dysregulated mitochondrial function has been linked to the initiation and progression of diverse human cancers. Deciphering the novel molecular mechanisms underlying mitochondrial function may provide important insights for developing novel therapeutics for CRPC. METHODS: RESULTS: We show that the increase of PPFIA4 exacerbates aggressive phenotype resembling CRPC. A fraction of PPFIA4 localizes to mitochondria and interacts with MTHFD2, a key enzyme for one- carbon metabolism. Androgen deprivation increases the translocation of PPFIA4 into mitochondria and increases the interaction between PPFIA4 and MTHFD2, which result in the elevation of tyrosine phosphorylated MTHFD2. Consequently, the levels of NADPH synthesis increase, resulting in protection against androgen deprivation-induced mitochondrial dysfunction, as well as promotion of tumor growth. Clinically, PPFIA4 expression is significantly increased in CRPC tissues compared with localized PCa ones. Importantly, an MTHFD2 inhibitor, DS18561882, combined with enzalutamide can significantly inhibit CRPC cell proliferation in vitro and tumor growth in vivo. CONCLUSION: Overall, our findings reveal a PPFIA4-MTHFD2 complex in mitochondria that links androgen deprivation to mitochondrial metabolism and mitochondrial dysfunction, which suggest a potential strategy to inhibit CRPC progression.
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Authors | Ru Zhao, Tingting Feng, Lin Gao, Feifei Sun, Qianqian Zhou, Xin Wang, Junmei Liu, Wenbo Zhang, Meng Wang, Xueting Xiong, Wenqiao Jia, Weiwen Chen, Lin Wang, Bo Han |
Journal | Journal of experimental & clinical cancer research : CR
(J Exp Clin Cancer Res)
Vol. 41
Issue 1
Pg. 125
(Apr 05 2022)
ISSN: 1756-9966 [Electronic] England |
PMID | 35382861
(Publication Type: Journal Article)
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Copyright | © 2022. The Author(s). |
Chemical References |
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Topics |
- Androgen Antagonists
- Animals
- Cell Line, Tumor
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- Mice
- Mitochondria
(metabolism)
- Prostatic Neoplasms, Castration-Resistant
(drug therapy, genetics, pathology)
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