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

Semenas, Julius LU ; Wang, Tianyan ; Sajid Syed Khaja, Azharuddin LU ; Firoj Mahmud, A. K.M. ; Simoulis, Athanasios LU orcid ; Grundström, Thomas ; Fällman, Maria and Persson, Jenny L. LU (2021) In Molecular Oncology 15(4). p.968-986
Abstract

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... (More)

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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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
castration-resistant prostate cancer, estrogen receptor, PI3K/AKT pathway and tamoxifen, PIP5K1α, targeted therapy
in
Molecular Oncology
volume
15
issue
4
pages
19 pages
publisher
Elsevier
external identifiers
  • scopus:85097594187
  • pmid:33275817
ISSN
1574-7891
DOI
10.1002/1878-0261.12873
language
English
LU publication?
yes
id
938c11f7-f535-49f5-9f6b-d0b51121be29
date added to LUP
2021-12-08 15:07:59
date last changed
2024-04-20 17:14:34
@article{938c11f7-f535-49f5-9f6b-d0b51121be29,
  abstract     = {{<p>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.</p>}},
  author       = {{Semenas, Julius and Wang, Tianyan and Sajid Syed Khaja, Azharuddin and Firoj Mahmud, A. K.M. and Simoulis, Athanasios and Grundström, Thomas and Fällman, Maria and Persson, Jenny L.}},
  issn         = {{1574-7891}},
  keywords     = {{castration-resistant prostate cancer; estrogen receptor; PI3K/AKT pathway and tamoxifen; PIP5K1α; targeted therapy}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{968--986}},
  publisher    = {{Elsevier}},
  series       = {{Molecular Oncology}},
  title        = {{Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration-resistant prostate cancer}},
  url          = {{http://dx.doi.org/10.1002/1878-0261.12873}},
  doi          = {{10.1002/1878-0261.12873}},
  volume       = {{15}},
  year         = {{2021}},
}