Abstract 1011: Endostatin regulates androgen receptor-mediated metabolic and oxido-reductive pathways in prostate cancer cells

Endostatin (ES) has been recognized for decades as an endogenous protein with antiangiogenic function. Recent findings, however, indicate the pleiotropic effects of ES in different tissue and cell types, ensuing further investigation on unidentified molecular mechanisms of action. Previously, we have shown that ES exerts a direct role in suppressing prostate cancer cell proliferation by inhibiting androgen receptor (AR) activity, signifying therapeutic potential of ES for targeting both tumor epithelia and endothelia. Subsequent to this finding, we identified robust glucose influx and significant reduction of intracellular ROS levels in LNCaP cells upon ES treatment. The ES mutants with low AR binding did not promote glucose uptake through GLUT1 augmentation, suggesting that AR-targeted effects of ES include modulation of downstream metabolic pathways. Surprisingly, global proteome analysis showed that the levels of major metabolic enzymes either in glycolytic pathway or TCA cycle were not changed upon ES treatment. Instead, ES markedly increased the levels of G6PD (5-fold), NAMPT (2.5-fold), and NAPRT (5-fold), indicating upregulation of the late-limiting steps in NAD biosynthesis and pentose phosphate pathway (PPP). Further proteome analysis of ES-treated LNCaP cells strongly indicated upregulation of ROS scavenging machinery, including SOD2 (3- fold), CAT (2-folds), GSS (2-fold), GSR (1.8-fold), and POR (4.6-fold). Overall, these data suggest that ES can modulate intracellular ROS levels by augmenting glucose uptake, NAD biosynthesis, and the NADPH levels by shunting metabolic pathways to PPP. Given that basal ROS levels are known to increase upon disease progression to higher grade prostate tumors, ES effect of promoting ROS scavenging machinery can be employed as an adjuvant to re-sensitize prostate cancer cells to ROS-inducing chemo- and radiation therapies. Abbreviations: CAT: catalase, GLUT1: glucose transporter isoform 1, G6PD: glucose-6-phosphate dehydrogenase, GSS: glutathione synthase, GSR: glutathione reductase, NAMPT: nicotinamide phosphoribosyltransferase, NAPRT: nicotinate phosphoribosyltransferase, POR: NADPH-cytochrome P450 reductase, ROS: reactive oxygen species, SOD2: manganese superoxide dismutase, TCA: tricarboxylic acid Citation Format: Joo Hyoung Lee, Minsung Kang, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan. Endostatin regulates androgen receptor-mediated metabolic and oxido-reductive pathways in prostate cancer cells. [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 1011.