Erg Oncogenic Activation Leads To The Endoplasmic Reticulum Stress And Cell Survival Mechanisms

Abstract Introduction: High levels of the ERG expression due to gene fusions (predominantly TMPRSS2-ERG) is frequently detected in prostate cancer (CaP) in Western countries. Better understanding of the roles of the ERG oncogenic functions in CaP initiation and/or progression will enhance its utility as the therapeutic target. Transgenic mice generated to understand role of ERG in the CaP development have shown focal proliferative and dysplastic PIN lesions and adenocarcinoma in older mice. The present study was aimed towards understanding the molecular mechanism underlying the role of ERG in early stages of oncogenic transformation of prostate epithelium. Methods: Morphological analyses of mouse prostate glands were performed by H&E staining and by electron microscopy. Luminal cell surface markers were evaluated by FACS analysis. Luminal cells were assessed for their potential to proliferate and form spheres by prostate sphere formation assay. Effects of ERG on ER stress and UPR marker proteins were analyzed in transgenic mice prostates and ERG expressing cell culture models. Representative ER stress pathway in ERG-positive human prostate cancer was analyzed by CPDR-Affymetrix GeneChip data from well and poorly differentiated tumors. Results: Histological examination of ERG-Tg mouse prostates revealed increased luminal cell death due to apoptosis. Subsequently, TEM analysis revealed significant morphological differences such as increased numbers of lysosomes, autophagosomes, concentric membrane bodies with ribosomes, and lipid droplets in the cytoplasm of transgenic secretory luminal epithelial cells. Epithelial cells of ERG-Tg mouse prostates showed increase in CD49f (low) and Sca-1 (med) population with increased sphere formation capability and resistance to induced cell death. ERG-Tg mouse prostate tissues and LNCaP-ERG transfectants showed increased expression of ER stress sensors and UPR proteins. Further, in human prostate tumors, a strong correlation was also observed between expression of the ERG and P4HB/PDI, an ER stress response protein. Conclusions: A critical of function of ERG in early prostate tumorigenesis may involve ER stress resulting into the activation of UPR, autophagy and cell survival through clonal selection. These observation also define potential new therapeutic targets in CaP-ERG network. Funding: This research in part was supported by the National Cancer Institute R01CA162383 (S. S.) and USU-CPDR funds. Citation Format: Taduru L. Sreenath, Shiela Macalindong, Natallia Mikhalkevich, Shashwat Sharad, Parameet Kumar, Denise Young, Rishita Gupta, Shilpa Katta, Ahmed Mohamed, Shyh-Han Tan, Albert Dobi, Gyorgy Petrovics, Isabell A. Sesterhenn, Charles J. Bieberich, Peter Nelson, David G. McLeod, Valeri Vasioukhin, Shiv Srivastava. ERG oncogenic activation leads to the endoplasmic reticulum stress and cell survival mechanisms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4175.