Journal Article

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

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

2021

Overview

In the present study, we unrevealed the effect of tamoxifen on ERα and PIP5K1α/AKT that are responsible for prostate cancer growth and invasion. Tamoxifen in combination treatment with PIP5K1α inhibitor, ISA‐2011B, led to tumor regression in xenograft mice. We found that depletion of tumor‐associated macrophages using clodronate sensitized the inhibitory effect of tamoxifen on 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. 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.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: 17β-Estradiol / AKT protein / Androgens / Animal welfare / Animals / Apoptosis / Bioinformatics / Breast cancer / Cancer and Oncology / Cancer och onkologi / Cancer therapies / Castration / Castration-resistant prostate cancer / Clinical Medicine / Copy number / Diketopiperazines - therapeutic use / DNA methylation / estrogen receptor / Estrogen Receptor alpha - antagonists & inhibitors / Estrogens / Gene expression / Genomes / Humans / Indoles - therapeutic use / Isoquinolines - therapeutic use / Kinases / Klinisk medicin / Ligands / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Metastases / Metastasis / Mice / Mice, Nude / Ontology / Patients / PC-3 Cells / Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors / PI3K/AKT pathway and tamoxifen / PIP5K1α / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Proto-Oncogene Proteins c-akt / RNA-Seq / Signal Transduction - drug effects / Skeleton / Software / Tamoxifen / Tamoxifen - therapeutic use / targeted therapy / Tetrahydroisoquinoline / Tumors / Xenograft Model Antitumor Assays