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Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).ORCID-id: 0000-0001-5394-7239
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).ORCID-id: 0000-0003-0155-7639
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).ORCID-id: 0000-0003-1594-1826
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2021 (Engelska)Ingår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 15, nr 4, s. 968-986Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Selective ERα modulator, tamoxifen, is well tolerated in a heavily pretreated castration‐resistant prostate cancer (PCa) patient cohort. However, its targeted gene network and whether expression of intratumor ERα due to androgen‐deprivation therapy (ADT) may play a role in PCa progression is unknown. In this study, we examined the inhibitory effect of tamoxifen on castration‐resistant PCa in vitro and in vivo. We found that tamoxifen is a potent compound that induced a high degree of apoptosis and significantly suppressed growth of xenograft tumors in mice, at a degree comparable to ISA‐2011B, an inhibitor of PIP5K1α that acts upstream of PI3K/AKT survival signaling pathway. Moreover, depletion of tumor‐associated macrophages using clodronate in combination with tamoxifen increased inhibitory effect of tamoxifen on aggressive prostate tumors. We showed that both tamoxifen and ISA‐2011B exert their on‐target effects on prostate cancer cells by targeting cyclin D1 and PIP5K1α/AKT network and the interlinked estrogen signaling. Combination treatment using tamoxifen together with ISA‐2011B resulted in tumor regression and had superior inhibitory effect compared with that of tamoxifen or ISA‐2011B alone. We have identified sets of genes that are specifically targeted by tamoxifen, ISA‐2011B or combination of both agents by RNA‐seq. We discovered that alterations in unique gene signatures, in particular estrogen‐related marker genes are associated with poor patient disease‐free survival. We further showed that ERα interacted with PIP5K1α through formation of protein complexes in the nucleus, suggesting a functional link. Our finding is the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα, PIP5K1α/AKT network and MMP9/VEGF signaling axis, providing a strategy to treat castration‐resistant ER‐positive subtype of prostate cancer tumors with metastatic potential.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2021. Vol. 15, nr 4, s. 968-986
Nyckelord [en]
Castration-resistant prostate cancer, PI3K/AKT pathway and tamoxifen, PIP5K1α, estrogen receptor, targeted therapy
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-177666DOI: 10.1002/1878-0261.12873ISI: 000599152900001PubMedID: 33275817Scopus ID: 2-s2.0-85097594187OAI: oai:DiVA.org:umu-177666DiVA, id: diva2:1510564
Forskningsfinansiär
Cancerfonden, CAN-2017-381Vetenskapsrådet, 2019-01318Tillgänglig från: 2020-12-16 Skapad: 2020-12-16 Senast uppdaterad: 2022-12-15Bibliografiskt granskad

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Semenas, JuliusWang, TianyanKhaja, Azharuddin Sajid SyedMahmud, A. K. M. FirojGrundström, ThomasFällman, MariaPersson, Jenny L.

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Semenas, JuliusWang, TianyanKhaja, Azharuddin Sajid SyedMahmud, A. K. M. FirojGrundström, ThomasFällman, MariaPersson, Jenny L.
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Institutionen för molekylärbiologi (Medicinska fakulteten)
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Molecular Oncology
Cancer och onkologi

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