Abstract 1008: Resveratrol causes biphasic apoptotic and proliferative effects and at higher/proapoptotic/anti-angiogenesis concentrations causes suppression of nitric oxide/cGMP/protein kinase G signaling and decreased expression of prosurvival proteins c-IAP1, c-IAP2, livin and XIAP in human umbilical vein endothelial cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Anti-cancer/anti-angiogenesis effects of resveratrol have been reported. Resveratrol increases nitric oxide (NO) production via increased expression of endothelial-form-NO-synthase (eNOS). However, the role of cGMP/protein kinase G (PKG) signaling, a pathway activated by NO/eNOS, in the anti-angiogenic effects of resveratrol is still unclear. In the present study, involvement of endogenous NO/cGMP/PKG pathway and downstream pro-survival proteins (Inhibitor of Apoptosis Proteins, IAPs) are studied in relation to anti-angiogenic effects of resveratrol in human umbilical vein endothelial cells (HUVECs). Our results show that resveratrol at higher/anti-angiogenesis concentrations (>50 μM) inhibits tube formation and cell migration/invasion. Resveratrol stimulates proliferation/DNA synthesis at lower concentration (10 µM), but inhibits proliferation/DNA synthesis at higher concentrations (100 and 500 µM). Moreover, resveratrol at lower concentrations (10, 20 and 50 µM) protects HUVECs against spontaneous apoptosis, but induces higher-level apoptosis at higher concentration (500 µM). ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), inhibitor of endogenous NO-induced activation of soluble-guanylyl-cyclase and subsequent cGMP biosynthesis, completely abolishes the anti-apoptotic/cytoprotective effects of low-concentration resveratrol. 8-Br-cGMP, a direct stimulator of PKG kinase-activity, protects against pro-apoptotic effects of high-concentration resveratrol, establishing a cytoprotective role of activated-PKG in HUVECs. Western blot analyses show that higher/pro-apoptotic/anti-angiogenesis concentrations of resveratrol cause suppression of PKG kinase-activity (indicated by decreased VASP phosphorylation at Ser239) and decreased expression of eNOS and four IAPs, c-IAP1, c-IAP2, livin and XIAP. Overall, our results suggest a cytoprotective role of NO/cGMP/PKG signaling in HUVECs and further suggest that resveratrol (>50 μM)-induced anti-angiogenesis/pro-apoptosis involves suppression of NO/cGMP/PKG signaling and decreased expression of pro-survival proteins c-IAP1, c-IAP2, livin and XIAP. Citation Format: Janica C. Wong, Renee Coffman, Harry Rosenberg, Ronald R. Fiscus. Resveratrol causes biphasic apoptotic and proliferative effects and at higher/proapoptotic/anti-angiogenesis concentrations causes suppression of nitric oxide/cGMP/protein kinase G signaling and decreased expression of prosurvival proteins c-IAP1, c-IAP2, livin and XIAP in human umbilical vein endothelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1008. doi:10.1158/1538-7445.AM2014-1008