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Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer

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...

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Autores principales: Semenas, Julius, Wang, Tianyan, Sajid Syed Khaja, Azharuddin, Firoj Mahmud, AKM, Simoulis, Athanasios, Grundström, Thomas, Fällman, Maria, Persson, Jenny L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024724/
https://www.ncbi.nlm.nih.gov/pubmed/33275817
http://dx.doi.org/10.1002/1878-0261.12873
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author Semenas, Julius
Wang, Tianyan
Sajid Syed Khaja, Azharuddin
Firoj Mahmud, AKM
Simoulis, Athanasios
Grundström, Thomas
Fällman, Maria
Persson, Jenny L.
author_facet Semenas, Julius
Wang, Tianyan
Sajid Syed Khaja, Azharuddin
Firoj Mahmud, AKM
Simoulis, Athanasios
Grundström, Thomas
Fällman, Maria
Persson, Jenny L.
author_sort Semenas, Julius
collection PubMed
description 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.
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spelling pubmed-80247242021-04-12 Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer Semenas, Julius Wang, Tianyan Sajid Syed Khaja, Azharuddin Firoj Mahmud, AKM Simoulis, Athanasios Grundström, Thomas Fällman, Maria Persson, Jenny L. Mol Oncol Research Articles 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. John Wiley and Sons Inc. 2020-12-16 2021-04 /pmc/articles/PMC8024724/ /pubmed/33275817 http://dx.doi.org/10.1002/1878-0261.12873 Text en © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Semenas, Julius
Wang, Tianyan
Sajid Syed Khaja, Azharuddin
Firoj Mahmud, AKM
Simoulis, Athanasios
Grundström, Thomas
Fällman, Maria
Persson, Jenny L.
Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
title Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
title_full Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
title_fullStr Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
title_full_unstemmed Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
title_short Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
title_sort targeted inhibition of erα signaling and pip5k1α/akt pathways in castration‐resistant prostate cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024724/
https://www.ncbi.nlm.nih.gov/pubmed/33275817
http://dx.doi.org/10.1002/1878-0261.12873
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