Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner.
10.1016/j.apsb.2021.09.007
- Author:
Cancan ZHENG
1
;
Xiaomei YU
1
;
Yiyao LIANG
2
;
Yidong ZHU
3
;
Yan HE
3
;
Long LIAO
1
;
Dingkang WANG
1
;
Yanming YANG
1
;
Xingfeng YIN
1
;
Ang LI
2
;
Qingyu HE
1
;
Bin LI
1
Author Information
1. MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, China.
2. Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration, Ministry of Education, Jinan University, Guangzhou 510632, China.
3. MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
- Publication Type:Journal Article
- Keywords:
DARTS technology;
Drug repurposing;
Esophageal cancer;
Glycolysis;
Metabolic reprogramming;
PFKL;
Penfluridol
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1271-1287
- CountryChina
- Language:English
-
Abstract:
As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.
