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

Julius Semenas, Tianyan Wang, Azharuddin Sajid Syed Khaja, A. K.M. Firoj Mahmud, Athanasios Simoulis, Thomas Grundström, Maria Fällman, Jenny L. Persson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)968-986
Number of pages19
JournalMolecular Oncology
Issue number4
Publication statusPublished - 2021

Subject classification (UKÄ)

  • Cancer and Oncology

Free keywords

  • castration-resistant prostate cancer
  • estrogen receptor
  • PI3K/AKT pathway and tamoxifen
  • PIP5K1α
  • targeted therapy


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