Theranostics 2020; 10(6):2571-2586. doi:10.7150/thno.42874

Research Paper

Mitochondrial PAK6 inhibits prostate cancer cell apoptosis via the PAK6-SIRT4-ANT2 complex

Tingting Li1, Yang Li1, Tong Liu2, Bingtao Hu1, Jiabin Li1, Chen Liu1, Tao Liu3✉, Feng Li1✉

1. Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the PRC, and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, Shenyang 110122, Liaoning, China.
2. Medical Research Center, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China.
3. Department of Urology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China.

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Citation:
Li T, Li Y, Liu T, Hu B, Li J, Liu C, Liu T, Li F. Mitochondrial PAK6 inhibits prostate cancer cell apoptosis via the PAK6-SIRT4-ANT2 complex. Theranostics 2020; 10(6):2571-2586. doi:10.7150/thno.42874. Available from http://www.thno.org/v10p2571.htm

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Abstract

Rationale: P21-activated kinase 6 (PAK6) is a member of the class II PAKs family, which is a conserved family of serine/threonine kinases. Although the effects of PAK6 on many malignancies, especially in prostate cancer, have been studied for a long time, the role of PAK6 in mitochondria remains unknown.

Methods: The expression of PAK6, SIRT4 and ANT2 in prostate cancer and adjacent non-tumor tissues was detected by immunohistochemistry. Immunofuorescence and immunoelectron microscopy were used to determine the subcellular localization of PAK6. Immunoprecipitation, immunofuorescence and ubiquitination assays were performed to determine how PAK6 regulates SIRT4, how SIRT4 regulates ANT2, and how PAK6 regulates ANT2. Flow cytometry detection and xenograft models were used to evaluate the impact of ANT2 mutant expression on the prostate cancer cell cycle and apoptosis regulation.

Results: The present study revealed that the PAK6-SIRT4-ANT2 complex is involved in mitochondrial apoptosis in prostate cancer cells. It was found that PAK6 is mainly located in the mitochondrial inner membrane, in which PAK6 promotes SIRT4 ubiquitin-mediated proteolysis. Furthermore, SIRT4 deprives the ANT2 acetylation at K105 to promote its ubiquitination degradation. Hence, PAK6 adjusts the acetylation level of ANT2 through the PAK6-SIRT4-ANT2 pathway, in order to regulate the stability of ANT2. Meanwhile, PAK6 directly phosphorylates ANT2 atT107 to inhibit the apoptosis of prostate cancer cells. Therefore, the phosphorylation and deacetylation modifications of ANT2 are mutually regulated, leading to tumor growth in vivo. Consistently, these clinical prostate cancer tissue evaluations reveal that PAK6 is positively correlated with ANT2 expression, but negatively correlated with SIRT4.

Conclusion: These present findings suggest the pivotal role of the PAK6-SIRT4-ANT2 complex in the apoptosis of prostate cancer. This complex could be a potential biomarker for the treatment and prognosis of prostate cancer.

Keywords: PAK6, SIRT4, ANT2, apoptosis, prostate cancer.