RIPK3 overcomes 5-fluorouracil resistance in colorectal cancer cells via AKT/mTOR-mediated autophagy

Abstract Colorectal carcinoma (CRC) is one of the most prevalent malignant tumors globally, with high morbidity and mortality rates. 5-Fluorouracil (5-FU) remains the standard first-line chemotherapy for CRC; however, the increasing development of 5-FU resistance poses a significant challenge. In this study, RIPK3 was identified as a potential anti-drug resistance target through biosignature analysis. In colorectal cancer tissues, RIPK3 expression was downregulated, and patients with low RIPK3 expression levels exhibited significantly shorter overall and disease-free survival. The expression of RIPK3 was notably reduced in the 5-FU-resistant HCT8R cells compared to the 5-FU-sensitive HCT8 cells. Knockdown of RIPK3 in HCT8 cells restored cell proliferation, migration, and invasion, which were inhibited by 5-FU, and promoted the development of cellular drug resistance. Conversely, overexpression of RIPK3 in HCT8R cells enhanced the 5-FU-induced inhibition of cell proliferation, migration, and invasion, thereby reducing cellular resistance to the drug. Further mechanistic studies revealed that RIPK3 facilitated cellular autophagy by inhibiting the AKT-mTOR signaling pathway. Collectively, RIPK3 enhances the sensitivity of colorectal cancer cells to 5-FU and increases the efficacy of 5-FU in inhibiting cell proliferation, invasion, and migration by activating cellular autophagy through inhibition of the AKT-mTOR signaling pathway, thereby reversing drug resistance in colorectal cancer cells.