Abstract 2765: Novel WNT-RIP1-GDF15 pathway promotes migration and invasion of colorectal cancer cells

Abstract

Abstract Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor β (TGF-β) family protein, also known as NSAID-activated gene 1 (NAG-1) or macrophage inhibitory cytokine 1 (MIC-1), and is a major cause of cancer cachexia, cardiovascular disease, and various inflammatory diseases. Roles of GDF15 as major inflammatory response factor also have been demonstrated in animal models, and it has also showed various malignant functions such as regulating metabolism, promoting metastasis by inducing EMT in cancer. Here, we revealed a novel potential role for RIP1 in colorectal cancer (CRC) in enhancing metastasis by controlling WNT-RIP1-GDF15 signaling. We showed that WNT3A treatment increased the expression of GDF15 and GFRAL. Immunohistochemical analysis of human CRC tissue arrays consisting of primary cancer and metastatic cancer also confirmed that the expression of GDF15 and GFRAL was increased in metastatic cancer. Human XL cytokine assay, western blot, and ELISA results confirmed that GDF15 expression was reduced in cell lines in which RIP1 was knocked down. Reduction of GDF15 expression and secretion by RIP1 knockdown showed suppression of EMT induction resulting to decrease of migration and invasion of CRC cells. Taken together, these results suggest a novel EMT-enhancing role for RIP1 in the WNT pathway and suggest a novel WNT-RIP1-GDF15 pathway contributing to CRC malignancy by promoting EMT. Citation Format: A-Ram Kang, Do Hoon Kim, Jong Kuk Park. Novel WNT-RIP1-GDF15 pathway promotes migration and invasion of colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2765.