Abstract A45: A potential therapeutic strategy for treatment of colorectal cancers through regulating Ras stability via inhibition of Wnt/β-catenin pathway

Abstract

Abstract Ras is a well-characterized proto-oncogene, and its various mutations contribute to transformation and tumorigenesis in a wide variety of human cancers. Although the GTP/GDP loading switch is known as a major regulatory mechanism of Ras, other mechanisms affecting Ras activity are poorly understood. Here, we report a mechanism for controlling Ras activity by regulating its degradation and describe this regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/β-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras following phosphorylation by glycogen synthase kinase 3β (GSK3β) and subsequent recruitment of β-TrCP-E3 ligase. We found a positive association between tumorigenesis and Ras stabilization due to the aberrant activation of Wnt/β-catenin signaling. Our results indicate an essential role for phosphorylation and degradation of Ras and suppression of Ras-induced transformation via the Wnt/β-catenin pathway and provide insight into the role of this novel regulatory mechanism for Ras in tumorigenesis of colorectal cancers (CRCs). Because both Ras and Wnt/β-catenin pathways are frequently activated in CRCs, these results suggest that the regulation of Ras stability through inhibition of the Wnt/β-catenin pathway could be an ideal therapeutic approach for treatment of CRC. Citation Format: Pu-Hyeon Cha, Yong-Hee Cho, Woo-Jeong Jeong, Kang-Yell Choi. A potential therapeutic strategy for treatment of colorectal cancers through regulating Ras stability via inhibition of Wnt/β-catenin pathway. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A45. doi: 10.1158/1557-3125.RASONC14-A45