MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling
Abstract Background Over-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 dephospho...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-019-0355-1 |
| _version_ | 1828851568010592256 |
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| author | Guang Yan Yi Ru Fengqi Yan Xin Xiong Wei Hu Tao Pan Jianming Sun Chi Zhang Qinhao Wang Xia Li |
| author_facet | Guang Yan Yi Ru Fengqi Yan Xin Xiong Wei Hu Tao Pan Jianming Sun Chi Zhang Qinhao Wang Xia Li |
| author_sort | Guang Yan |
| collection | DOAJ |
| description | Abstract Background Over-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. Results We 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. Conclusion We 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. |
| first_indexed | 2024-12-12T23:35:14Z |
| format | Article |
| id | doaj.art-a5f6b6a7b27141d2be68d543027579c3 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-12T23:35:14Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-a5f6b6a7b27141d2be68d543027579c32022-12-22T00:07:32ZengBMCCell Communication and Signaling1478-811X2019-05-0117111410.1186/s12964-019-0355-1MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signalingGuang Yan0Yi Ru1Fengqi Yan2Xin Xiong3Wei Hu4Tao Pan5Jianming Sun6Chi Zhang7Qinhao Wang8Xia Li9State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical UniversityDepartment of Urology, Tangdu Hospital, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical UniversityAndrology Department, Shanghai Seventh People’s HospitalRehabilitation Department, Gongli Hospital of Shanghai Pudong New AreaState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical UniversityAbstract Background Over-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. Results We 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. Conclusion We 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.http://link.springer.com/article/10.1186/s12964-019-0355-1MIIPProliferationProstate cancerPP1αPI3K-AKT-mTOR |
| spellingShingle | Guang Yan Yi Ru Fengqi Yan Xin Xiong Wei Hu Tao Pan Jianming Sun Chi Zhang Qinhao Wang Xia Li MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling Cell Communication and Signaling MIIP Proliferation Prostate cancer PP1α PI3K-AKT-mTOR |
| title | MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling |
| title_full | MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling |
| title_fullStr | MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling |
| title_full_unstemmed | MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling |
| title_short | MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling |
| title_sort | miip inhibits the growth of prostate cancer via interaction with pp1α and negative modulation of akt signaling |
| topic | MIIP Proliferation Prostate cancer PP1α PI3K-AKT-mTOR |
| url | http://link.springer.com/article/10.1186/s12964-019-0355-1 |
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