Targeting the JAK2–STAT3–UCHL3–ENO1 axis suppresses glycolysis and enhances the sensitivity to 5-FU chemotherapy in TP53-mutant colorectal cancer
Haisong Xin, Zitong Zhao, Shichao Guo, Ruoxi Tian, Liying Ma, Yang Yang, Lianmei Zhao, Guanglin Wang, Guanglin Wang, Baokun Li, Xuhua Hu, Yongmei Song, Guiying Wang, Guiying Wang
Abstract
Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53 -mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α -enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)–signal transducer and activator of transcription 3 (STAT3) pathway in TP 53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53 -mutant CRC. Our findings suggest that targeting the JAK2–STAT3–UCHL3–ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53 -mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53 -mutant CRC. Targeting the JAK2–STAT3–UCHL3–ENO1 axis is a promising strategy to suppress glycolysis and enhance the sensitivity of 5-FU chemotherapy in TP53 -mutant CRC. Pacritinib shows the potential for clinical application in treating TP53 -mutant CRC.