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The functional interlink between AR and MMP9/VEGF signaling axis is mediated through PIP5K1α/pAKT in prostate cancer
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). 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 universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2020 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, nr 6, s. 1686-1699Artikel i tidskrift (Refereegranskat) Published
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 PIP5K1α/AK. We showed that MMP9 physically interacted with PIP5K1α 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/PIP5K1α/AKT/MMP9/VEG signaling axis contributed to increased invasiveness and growth of metastatic tumors. Conversely, treatment with PIP5K1α 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 PIP5K1α/AKT pathways using PIP5K1α inhibitor in metastatic PCa.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2020. Vol. 146, nr 6, s. 1686-1699
Nyckelord [en]
matrix metalloproteinases 9, AKT, androgen receptor, metastatic prostate cancer, targeted therapy
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-162846DOI: 10.1002/ijc.32607ISI: 000481247000001PubMedID: 31381135Scopus ID: 2-s2.0-85071148602OAI: oai:DiVA.org:umu-162846DiVA, id: diva2:1350362
Forskningsfinansiär
Barncancerfonden, TJ2015-0097Cancerfonden, 170621KempestiftelsernaTillgänglig från: 2019-09-11 Skapad: 2019-09-11 Senast uppdaterad: 2022-12-15Bibliografiskt granskad
Ingår i avhandling
1. Targeted therapeutic strategies for prostate cancer treatment using novel lipid kinase inhibitors in combination with current drugs
Öppna denna publikation i ny flik eller fönster >>Targeted therapeutic strategies for prostate cancer treatment using novel lipid kinase inhibitors in combination with current drugs
2020 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Prostate cancer (PCa) is one of the most common cancer types and the fifth cancer-related cause of death among Western world men.  The sex steroid hormone, androgen and androgen receptor (AR) play important roles in PCa progression. Herewith, androgen deprivation therapy (ADT) is used as a regimen for PCa, but inevitably leads to development of castration-resistant PCa (CRPC) and distant metastasis. No effective treatment for metastatic PCa currently exists. Furthermore, it remains poorly understood whether and how the steroid hormone signaling in cooperation with multiple pathways that control proliferation, survival and invasion of cancer cells may contribute to metastatic dissemination and growth.

The aims of my PhD thesis focused on: (i) studying the clinical importance of estrogen- and androgen-related signaling pathways in promoting homing and metastatic growth of PCa cells in bone, (ii) gaining deeper understanding of the underlying mechanisms that facilitate PCa metastasis and treatment resistance, with focus on phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1α), estrogen- and androgen receptor signaling, (iii) testing and characterizing the therapeutic potential of PIP5K1α inhibitor in combination with anti-estrogen or anti-androgen agents to improve treatment and overcome treatment resistance in CRPC.

In my thesis work we have shown that key biomarker genes exhibited unique expression profiles and signatures in PCa subtypes within large patient cohorts. Alterations in androgen- and estrogen-related biomarkers and PIP5K1α/Akt pathways were associated with poor patient outcome. We further discovered that CRPC cells and cancer stem-like cells utilized estrogen-associated factors including aromatase and estrogen receptor alpha (ERα), as well as cyclin A1, a key cell cycle regulator, to gain proliferative advantage, and to survive and metastasize to distant organs.

We found that the interaction between PIP5K1α and AR splice variant AR-V7 contributed to enzalutamide resistance. In series of in vivo treatment experiments using tumor xenograft mice, we demonstrated that ISA-2011B alone or in combination with enzalutamide had great therapeutic potential to suppress growth of tumors that had elevated levels of PI3K/Akt and AR-V7, and that were resistant to enzalutamide monotherapy.

We further showed that combination treatment using tamoxifen together with ISA-2011B selectively blocked elevated ERα/cyclin D1 and PIP5K1α/Akt, leading to tumor regression and had superior inhibitory effect over monotherapy in xenograft mice.

My studies therefore suggest that steroid hormone receptors, PIP5K1α signaling cascade and multiple cellular pathways cooperatively promote PCa progression. Taken together, the reported findings are the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα and PIP5K1α/Akt network, and provide a new therapeutic strategy to treat castration-resistant ER-positive subtype of tumors with metastatic potential.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2020. s. 70
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2084
Nyckelord
Prostate cancer, bone metastasis, castration-resistant, treatment, precision therapy, PIP5K1A, steroid hormone receptors, cancer stem cells
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
onkologi
Identifikatorer
urn:nbn:se:umu:diva-169646 (URN)978-91-7855-263-4 (ISBN)978-91-7855-264-1 (ISBN)
Disputation
2020-05-08, Hörsal 933, Unod B9, NUS, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2020-04-17 Skapad: 2020-04-14 Senast uppdaterad: 2020-04-14Bibliografiskt granskad

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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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