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...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Wiley
2021-04-01
|
Series: | Molecular Oncology |
Subjects: | |
Online Access: | https://doi.org/10.1002/1878-0261.12873 |
id |
doaj-76e6e359dd224187a7177058d52aa91f |
---|---|
record_format |
Article |
spelling |
doaj-76e6e359dd224187a7177058d52aa91f2021-04-07T06:04:57ZengWileyMolecular Oncology1574-78911878-02612021-04-0115496898610.1002/1878-0261.12873Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancerJulius Semenas0Tianyan Wang1Azharuddin Sajid Syed Khaja2AKM Firoj Mahmud3Athanasios Simoulis4Thomas Grundström5Maria Fällman6Jenny L. Persson7Department of Molecular Biology Umeå University SwedenDepartment of Molecular Biology Umeå University SwedenDepartment of Molecular Biology Umeå University SwedenDepartment of Molecular Biology Umeå University SwedenDepartment of Clinical Pathology and Cytology Skåne University Hospital Malmö SwedenDepartment of Molecular Biology Umeå University SwedenDepartment of Molecular Biology Umeå University SwedenDepartment of Molecular Biology Umeå University SwedenSelective 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.https://doi.org/10.1002/1878-0261.12873castration‐resistant prostate cancerestrogen receptorPI3K/AKT pathway and tamoxifenPIP5K1αtargeted therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Julius Semenas Tianyan Wang Azharuddin Sajid Syed Khaja AKM Firoj Mahmud Athanasios Simoulis Thomas Grundström Maria Fällman Jenny L. Persson |
spellingShingle |
Julius Semenas Tianyan Wang Azharuddin Sajid Syed Khaja AKM Firoj Mahmud Athanasios Simoulis Thomas Grundström Maria Fällman Jenny L. Persson Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer Molecular Oncology castration‐resistant prostate cancer estrogen receptor PI3K/AKT pathway and tamoxifen PIP5K1α targeted therapy |
author_facet |
Julius Semenas Tianyan Wang Azharuddin Sajid Syed Khaja AKM Firoj Mahmud Athanasios Simoulis Thomas Grundström Maria Fällman Jenny L. Persson |
author_sort |
Julius Semenas |
title |
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_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_sort |
targeted inhibition of erα signaling and pip5k1α/akt pathways in castration‐resistant prostate cancer |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2021-04-01 |
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. |
topic |
castration‐resistant prostate cancer estrogen receptor PI3K/AKT pathway and tamoxifen PIP5K1α targeted therapy |
url |
https://doi.org/10.1002/1878-0261.12873 |
work_keys_str_mv |
AT juliussemenas targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer AT tianyanwang targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer AT azharuddinsajidsyedkhaja targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer AT akmfirojmahmud targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer AT athanasiossimoulis targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer AT thomasgrundstrom targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer AT mariafallman targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer AT jennylpersson targetedinhibitionoferasignalingandpip5k1aaktpathwaysincastrationresistantprostatecancer |
_version_ |
1721536431991554048 |