Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration-resistant prostate cancer
(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.
(Less)
- author
- Semenas, Julius LU ; Wang, Tianyan ; Sajid Syed Khaja, Azharuddin LU ; Firoj Mahmud, A. K.M. ; Simoulis, Athanasios LU ; Grundström, Thomas ; Fällman, Maria and Persson, Jenny L. LU
- organization
- publishing date
- 2021
- 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
- 2024-09-23 08:13:41
@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}}, }