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Targeted suppression of AR-V7 using PIP5K1 alpha inhibitor overcomes enzalutamide resistance in prostate cancer cells
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.
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 Genetics, Kazan Federal University, Kazan, Russia.
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2016 (Engelska)Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 7, nr 39, s. 63065-63081Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5K alpha), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5K alpha inhibitor highlight the potential of PIP5K1 alpha as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1 alpha in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1 alpha, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1 alpha by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1 alpha is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1 alpha and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1 alpha, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1 alpha may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.

Ort, förlag, år, upplaga, sidor
2016. Vol. 7, nr 39, s. 63065-63081
Nyckelord [en]
Prostate cancer metastasis, enzalutamide resistance, lipid kinase inhibitor, AR-V7, PIP5K1α
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-128475DOI: 10.18632/oncotarget.11757ISI: 000387167800020Scopus ID: 2-s2.0-84993967394OAI: oai:DiVA.org:umu-128475DiVA, id: diva2:1056647
Tillgänglig från: 2016-12-15 Skapad: 2016-12-05 Senast uppdaterad: 2024-01-17Bibliografiskt 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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