PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2

作者：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 · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2022 · DOI：10.1186/s13046-022-02331-3 · 被引用次数：43 · 研究领域：Protein Tyrosine Phosphatases、Hepatocellular Carcinoma Treatment and Prognosis、Prostate Cancer Treatment and Research

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: We investigate the expression of the protein tyrosine phosphatase receptor type F polypeptide interacting protein alpha 4 (PPFIA4) using public datasets and tumor specimens from PCa cases by immunohistochemistry. Gain- and loss-of-function studies are performed in PCa cell lines and mouse models of subcutaneous xenograft to characterize the role of PPFIA4 in CRPC. Gene expression regulation is evaluated by a series of molecular and biochemical experiments in PCa cell lines. The therapeutic effects of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) inhibitor combined enzalutamide are assessed using in vitro functional assays and in vivo mouse models. 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, t...