Abstract 1585: Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress

Abstract

Abstract Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to re-activation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa (CRPC). Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR), and downstream pro-oxidant signaling. This reversal following ES treatment significantly decreased PCa cell proliferation through downregulation of GR, and upregulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant upregulation of enzymes in major ROS scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented antioxidant system through upregulation of glucose influx, pentose phosphate pathway (PPP) and NAD salvaging pathway. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced CRPC phenotype upon AR antagonism, and dual targeting action of ES on AR and GR can be further translated to PCa therapy. Citation Format: Joo Hyoung Lee, Minsung Kang, Gurudatta Naik, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1585. doi:10.1158/1538-7445.AM2017-1585