1. Academic Validation
  2. PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2

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

  • J Exp Clin Cancer Res. 2022 Apr 5;41(1):125. doi: 10.1186/s13046-022-02331-3.
Ru Zhao 1 Tingting Feng 1 Lin Gao 1 Feifei Sun 1 Qianqian Zhou 1 Xin Wang 1 Junmei Liu 2 Wenbo Zhang 1 Meng Wang 1 Xueting Xiong 3 Wenqiao Jia 4 Weiwen Chen 2 Lin Wang 5 Bo Han 6 7
Affiliations

Affiliations

  • 1 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 4 Department of Health Management CenterQilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 5 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. kecheng1216@163.com.
  • 6 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. boh@sdu.edu.cn.
  • 7 Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. boh@sdu.edu.cn.
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: 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, 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.

Keywords

CRPC; MTHFD2; PPFIA4; mitochondrial function.

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