Targeting the JAK2-STAT3-UCHL3-ENO1 axis suppresses glycolysis and enhances the sensitivity to 5-FU chemotherapy in TP53-mutant colorectal cancer.
10.1016/j.apsb.2025.03.041
- Author:
Haisong XIN
1
;
Zitong ZHAO
2
;
Shichao GUO
2
;
Ruoxi TIAN
3
;
Liying MA
2
;
Yang YANG
4
;
Lianmei ZHAO
5
;
Guanglin WANG
6
;
Baokun LI
6
;
Xuhua HU
6
;
Yongmei SONG
2
;
Guiying WANG
1
Author Information
1. Department of General Surgery, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
2. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
3. Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
4. Department of General Surgery, the Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.
5. Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
6. The Second Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
- Publication Type:Journal Article
- Keywords:
Chemotherapy resistance;
Colorectal cancer;
Glycolysis;
JAK2–STAT3 pathway;
Pacritinib;
Stem-like properties;
TP53 mutation;
UCHL3
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2529-2544
- CountryChina
- Language:English
-
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 TP53-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.
