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The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1 alpha/pAKT in prostate cancer
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Currently, no effective targeted therapeutics exists for treatment of metastatic prostate cancer (PCa). Given that matrix metalloproteinases 9 (MMP9) and its associated vascular endothelial growth factor (VEGF) are critical for tumor vascularization and invasion under castration-resistant condition, it is therefore of great importance to define the functional association and interplay between androgen receptor (AR) and MMP9 and their associated key survival and invasion pathways in PCa cells. Here, we found that there was a significant correlation between MMP9 and AR protein expression in primary and metastatic PCa tissues, and a trend that high level of MMP9 expression was associated with poor prognosis. We demonstrated that constitutive activation of AR increased expression of MMP9 and VEGF/VEGF receptors. We further showed that AR exerts its effect on MMP9/VEGF signaling axis through PIP5K1 alpha/AKT. We showed that MMP9 physically interacted with PIP5K1 alpha via formation of protein-protein complexes. Furthermore, elevated expression of MMP9 enhanced ability of AR to activate its target gene cyclin A1. The elevated sequential activation of AR/PIP5K1 alpha/AKT/MMP9/VEGF signaling axis contributed to increased invasiveness and growth of metastatic tumors. Conversely, treatment with PIP5K1 alpha inhibitor significantly suppressed invasiveness of PCa cells expressing constitutively activated AR, this was coincident with its inhibitory effect of this inhibitor on AR/MMP9/VEGF pathways. Our results suggest that AR and MMP9-associated network proteins may be effectively targeted by blocking PIP5K1 alpha/AKT pathways using PIP5K1 alpha inhibitor in metastatic PCa.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019.
Keywords [en]
matrix metalloproteinases 9, AKT, androgen receptor, metastatic prostate cancer, targeted therapy
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-162846DOI: 10.1002/ijc.32607ISI: 000481247000001PubMedID: 31381135OAI: oai:DiVA.org:umu-162846DiVA, id: diva2:1350362
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-09-11

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Larsson, PerKhaja, Azharuddin Sajid SyedSemenas, JuliusWang, TianyanHedblom, AndreasWai, Sun NyuntPersson, Jenny L.

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Larsson, PerKhaja, Azharuddin Sajid SyedSemenas, JuliusWang, TianyanSimoulis, AthanasiosHedblom, AndreasWai, Sun NyuntPersson, Jenny L.
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Department of Molecular Biology (Faculty of Medicine)
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International Journal of Cancer
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