Abstract 2583: Regulation of AKT-FoxO signaling by PKG2 inhibits colon cancer cell growth.

Abstract

Abstract Signaling through cGMP has emerged as a potentially important suppressor of tumorigenesis in the colon, but the mechanism is poorly defined. Studies of guanylyl-cyclase (GCC) knockout mice indicate that cGMP signaling suppresses proliferation in the colon epithelium, and more recently that inhibition of AKT has an important role. Type-2 cGMP-dependent protein kinase (PKG2) is a central effector of cGMP in the colon epithelium and is a likely mediator of the homeostatic effects of cGMP signaling. The present study sought to determine whether PKG2 can regulate AKT signaling in colon cancer cells and in the colon mucosa. Activation of PKG2 in LS174T and HT29 colon cancer cells inhibited cell proliferation and increased G1 arrest. PKG2 activation also inhibited AKT activity in these cells as determined by immunoblotting for phospho-AKT and downstream phospho-S6. Suggestive of a mechanism, analysis of upstream components revealed that PKG2 increased the levels of phosphatase and tensin homolog (PTEN). Central to the growth-promoting role of AKT signaling is the inactivation of forkhead transcription factors (FoxO), which regulate growth-inhibitory and pro-apoptotic target gene expression. Consistent with the inhibition of AKT signaling, activation of PKG2 significantly increased luciferase reporter activity driven by FoxO-responsive elements in colon cancer cells. This activation was associated with increased levels of several FoxO target genes, including catalase, p27kip. The regulation of AKT/FoxO pathway by PKG2 in vivo was supported by increased phospho-AKT levels, and reduced FoxO target gene expression in the colon mucosa of Prkg2-/- mice compared to wild type siblings. Moreover, activation of cGMP signaling in the colon mucosa led to increased expression of FoxO targets, and suppression of both proliferation and redox stress. Taken together these data define a novel signaling pathway in the colon epithelium, where of PKG2 leads to activation of FoxO. The established tumor suppressor role of the FoxO proteins highlights the potential therapeutic role for cGMP signaling in the prevention of colon cancer. Citation Format: Rui Wang, In-Kiu Kwon, Muhan Hu, Darren D. Browning. Regulation of AKT-FoxO signaling by PKG2 inhibits colon cancer cell growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2583. doi:10.1158/1538-7445.AM2013-2583