IDO1-mediated kynurenine production inhibits IGFBP5 signaling to promote 5-fluorouracil-induced senescence escape and chemoresistance in colorectal cancer.

Abstract

Cellular senescence is an irreversible state of growth arrest, and induction of senescence is considered a potential therapeutic strategy against cancer. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme catabolizing L-tryptophan into kynurenine, plays a key role in tumor immune tolerance. However, the roles of IDO1 in cellular senescence and chemoresistance remain elusive. Herein, we observed a significant elevation of IDO1 expression in colorectal cancer (CRC) tissues compared to non-neoplastic controls, based on both the GEPIA database and mouse model. Functionally, ectopic expression of IDO1 blunted 5-fluorouracil (5-FU)-induced cell senescence and rendered CRC cells more refractory towards 5-FU treatment, whereas IDO1 silencing resulted in opposing effects. Further studies demonstrated that IDO1 overexpression decreased the levels of senescent-related proteins, including p16, p21, p53, and cyclin D1. Mechanistically, the kynurenine released from IDO1-expressing CRC cells inhibited the IGFBP5/p53 signaling pathway, accounting for IDO1-mediated suppression of cell senescence and induction of chemoresistance. Collectively, these data revealed an unrecognized role of IDO1 in senescence escape and chemoresistance via releasing its catabolite kynurenine, implicating that therapeutically targeting IDO1 or IGFBP5/p53 signaling pathway holds great promise for CRC treatment.