Abstract A010: ETS-related gene mediated androgen receptor aggregation and endoplasmic reticulum stress in prostate cancer development

Abstract

Abstract Introduction: AR-mediated activation of ETS Related Gene (ERG) represents one of the most common and validated prostate cancer driver genes. Recently, we have shown novel morphologic phenotypes of endoplasmic reticulum (ER) stress in prostate glands of ARR2PB-ERG transgenic mouse. Since AR regulates ERG expression through TMPRSS2 promoter in human prostate cancer, we continue to investigate the post-translational interactions between ERG and AR leading to ER stress and subsequently to cell survival mechanisms. Understanding these mechanisms will potentially have major therapeutic implications. Methods: Light and electron microscopy were used to examine the morphologic and subcellular differences. AR aggregations, Co-IP and Proximal Ligation Assay for protein-protein interactions were studied in LNCaP, HEK293 cells. N-terminal and C-deletions of AR were utilized to identify specific AR domain interactions with ERG. Luminal cell surface markers on the isolated mouse prostate glands and spontaneously immortalized mouse prostate epithelial cells from ERG transgenic mouse (MoE1) were analyzed by FACS analysis. Results: Coexpression of ERG and AR showed significant aggregation of AR in filter assays. Co-IP experiments and PLA assays revealed that significant interactions occur through N-terminal domain of AR with ERG. Epithelial cells of ERG-Tg mouse prostates showed ~70% increase in CD49f (low) and Sca-1 (med) population with increased sphere formation capability and resistance to radiation-induced cell death. Both epithelial cells grown into spheres and established MoE1 cells displayed increased CD49f (low) and significant increase in the EpCAM negative population. Conclusions: Overall, our experiments demonstrate the mechanistic link that the physical interactions between ERG and AR lead to ER stress in prostate epithelium through AR misfolding/aggregation. Our observations of ERG-induced AR aggregation as one of the initial events that lead to ER stress and to cell survival indicate a critical function for ERG in the etiology of prostate cancer initiation and progression. Citation Format: Taduru L. Sreenath, Shiela S. Macalindong, Natallia Mikhalkevich, Shashwat Sharad, Ahmed Mohamed, Denise Young, Borbiev Talaibek, Charles Xavier, Rishita Gupta, Muhammad Jamal, Kevin Babcock, Shyh-Han Tan Tan, Marja T. Nevalainen, Albert Dobi, Gyorgy Petrovics, Isabell A. Sesterhenn, Inger L. Rosner, Charles J. Bieberich, Peter Nelson, Valeri Vasioukhin, Shiv Srivastava. ETS-related gene mediated androgen receptor aggregation and endoplasmic reticulum stress in prostate cancer development [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A010.