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RIP1 (receptor interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. We herein reveal new potential roles of RIP1 in controlling WNT/β-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). Firstly, we show that WNT3A treatment sequentially increases the expression levels of RIP1 and β-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary cancer, and metastatic cancer indicate that elevated RIP1 expression might be related to β-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells to mice demonstrates that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicate that WNT3A treatment induces direct binding between RIP1 and β-catenin, and that this stabilizes the β-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via down-regulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhances WNT3A-induced RIP1 and β-catenin protein expression and binding, and this stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration/invasion of CRC cells in vitro. The results of an in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verify the direct binding of RIP1 and β-catenin. Finally, RIP1 expression can destroy the β-catenin-β-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-β-catenin pathway that contributes to CRC malignancy by promoting EMT. Citation Format: Jong Kuk Park, A-Ram Kang, Jin-Hee Kwon. A novel RIP1-mediated canonical WNT signaling pathway promoting colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2552. |
