MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling

Cell Communication and Signaling

Wei Hu¹  Qinghao Wang²  Xin Xiong²  Xia Li²  Tao Pan²  Yi Ru²  Fengqi Yan³  Guang Yan⁴  Chi Zhang⁵  Jianming Sun⁶ 

[1] 0000 0004 1761 4404, grid.233520.5, Department of Urology, Tangdu Hospital, The Fourth Military Medical University, 710038, Xi’an, Shaanxi, China;0000 0004 1761 4404, grid.233520.5, State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 710032, Xi’an, Shaanxi, China;0000 0004 1761 4404, grid.233520.5, State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 710032, Xi’an, Shaanxi, China;0000 0004 1761 4404, grid.233520.5, Department of Urology, Tangdu Hospital, The Fourth Military Medical University, 710038, Xi’an, Shaanxi, China;0000 0004 1761 4404, grid.233520.5, State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 710032, Xi’an, Shaanxi, China;grid.452746.6, Andrology Department, Shanghai Seventh People’s Hospital, 200137, Shanghai, China;Rehabilitation Department, Gongli Hospital of Shanghai Pudong New Area, 200137, Shanghai, China;grid.452746.6, Andrology Department, Shanghai Seventh People’s Hospital, 200137, Shanghai, China;

关键词: MIIP;    Proliferation;    Prostate cancer;    PP1α;    PI3K-AKT-mTOR;   

DOI  :  10.1186/s12964-019-0355-1

来源: publisher

【 摘 要 】

BackgroundOver-activation of phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway is one of important mechanisms to promote castration resistant prostate cancer, the final stage of prostate cancer (PCa). Dysregulation of PP1-meditaed AKT dephosphorylation might contribute to such an event but is not fully understood. As a newly identified tumor suppressor, MIIP exerts its role in various types of cancer but has not been investigated in PCa.ResultsWe first demonstrated that overexpression of migration and invasion inhibitory protein (MIIP) in human PCa cell lines suppresses their growth while knockdown of MIIP does the opposite in vitro. Although MIIP has no effect on the expression of AR and its target genes or the nuclear translocation of AR in AR-positive PCa cells, MIIP overexpression significantly inhibits activation of AKT-mTOR pathway in both AR- positive and negative PCa cells whereas knockdown of MIIP enhances AKT-mTOR signaling. Using Western blot, immunofluorescence co-localization and co-immunoprecipitation analysis, we found that MIIP interacts with PP1α via its C-terminal part but does not affect its protein level. Importantly, silence of PP1α reversed the inhibitory effect of MIIP on AKT phosphorylation and cell growth in PCa cell lines, while MIIP∆C, which is incapable of interacting with PP1α, loses MIIP’s effect, suggesting that MIIP exerts its roles via interaction with PP1α. Further, MIIP overexpression inhibits the growth of both AR- positive and negative PCa xenograft in nude mice. Finally, immunohistochemical staining of PCa tissue microarray showed that MIIP expression level is downregulated in PCa and negatively correlated with Gleason score of PCa.ConclusionWe discovered that MIIP is a novel suppressor of oncogenic AKT-mTOR signaling in PCa by facilitating PP1-meditaed AKT dephosphorylation. Our study further emphasized the tumor suppressive role of MIIP and illustrated a novel mechanism.

【 授权许可】

CC BY