Abstract 1328: Cadmium-induced endoplasmic reticulum stress causes defective autophagy in human prostate carcinogenesis
Authors: Venkatesh Kolluru, Ashish Tyagi, Balaji Chandrasekaran, Murali K. Ankem, Chendil Damodaran
Journal: Cancer Research (2018)

Abstract Introduction: Exposure to cadmium (Cd) is associated with a spectrum of human pathogenesis including the prostate cancer (CaP). A clear dose-response relation between Cd-exposure and CaP have been reported in men exposed to Cd. However, the molecular mechanism underlying the malignant cell transformation following Cd exposure is yet to be determined. One of the possible mechanisms is that Cd causes endoplasmic reticulum (ER) stress, which further induces defective autophagy that plays a cytoprotective role in response to the misfolded and unfolded proteins that are formed during cellular transformation. Hence, the goal of this study is to investigate the underlying mechanism of how Cd causes malignant cell transformation (from normal to cancer cells) and on the development of tumorigenesis by the Cd-transformed cells. Methods: Normal prostate epithelial cells (RWPE-1) and Cd (10µM)-transforming prostate epithelial cells and cadmium-transformed prostate epithelial cells (CTPE) were utilized. Overexpression and/or silence ER-sensors, EGFR, and p62 were performed in above mention cell lines and subjected to cell viability, apoptosis, autophagy functional studies and Western blot analyses. For statistical analysis, data were analyzed using Student's ‘t' test with a p-value less than 0.05 considered significant. Results: Our preliminary results suggest that during cellular transformation, Cd exposure induced ER-stress, which triggered the phosphorylation of stress transducers including protein kinase R-like ER Kinase (PERK) and e1F2-α (eukaryotic translation initiation factor 2A-alpha). Phosphorylation resulted in the activation of ATF4 (Activating Transcription Factor 4) and autophagy induction thus enhancing protection of Cd-damaged cells. Further, inhibition of stress inducers (ATF4) or p62 by siRNA blocked the Cd-induced defective autophagy resulted in growth inhibition in transforming cells. Interestingly, in Cd-transformed cells, blocking EGFR activation by siRNA or pharmacological inhibitors significantly inhibited the growth, but not in the transforming cells suggesting that EGFR activation plays a critical role only after cellular transformation. Further, xenograft tumor tissues generated by Cd-transformed cells expressed high levels of ATF-4, EGFR, p62 and LC3B in correlation with in vitro findings. Moreover, increased expression of the proteins (ATF-4, EGFR, p62, and LC3B) in human CaP specimens correlates with Gleason sum in comparison with benign prostatic hyperplasia and “normal” adjacent tissues. Conclusions: The results suggest that ER stress responsible for the defective autophagy in Cd-induced transformation. This study highlights the better understanding of the complex interrelationship among prostate cancer phenotypes and the molecular, cellular, biochemical, and pathological changes associated with Cd and prostate cancer. Citation Format: Venkatesh Kolluru, Ashish Tyagi, Balaji Chandrasekaran, Murali K. Ankem, Chendil Damodaran. Cadmium-induced endoplasmic reticulum stress causes defective autophagy in human prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1328.