CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer.
10.1016/j.apsb.2024.12.019
- Author:
Yuncheng BEI
1
;
Sijie WANG
1
;
Rui WANG
1
;
Owais AHMAD
1
;
Meng JIA
2
;
Pengju YAO
3
;
Jianguo JI
3
;
Pingping SHEN
1
Author Information
1. Clinical Stem Cell Center, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
3. State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China.
- Publication Type:Journal Article
- Keywords:
Breast cancer;
CDK5;
Drug resistance;
Glucose-6-phosphoate dehydrogenase;
Intracellular redox homeostasis;
Isotopomer spectral analysis;
Olaparib;
Pentose phosphate pathway
- From:
Acta Pharmaceutica Sinica B
2025;15(3):1608-1625
- CountryChina
- Language:English
-
Abstract:
Glucose-6-phosphate dehydrogenase (G6PD), the first rate-limiting enzyme of the pentose phosphate pathway (PPP), is aberrantly activated in multiple types of human cancers, governing the progression of tumor cells as well as the efficacy of anticancer therapy. Here, we discovered that cyclin-dependent kinase 5 (CDK5) rewired glucose metabolism from glycolysis to PPP in breast cancer (BC) cells by activating G6PD to keep intracellular redox homeostasis under oxidative stress. Mechanistically, CDK5-phosphorylated G6PD at Thr-91 facilitated the assembly of inactive monomers of G6PD into active dimers. More importantly, CDK5-induced pho-G6PD was explicitly observed specifically in tumor tissues in human BC specimens. Pharmacological inhibition of CDK5 remarkably abrogated G6PD phosphorylation, attenuated tumor growth and metastasis, and synergistically sensitized BC cells to poly-ADP-ribose polymerase (PARP) inhibitor Olaparib, in xenograft mouse models. Collectively, our results establish the crucial role of CDK5-mediated phosphorylation of G6PD in BC growth and metastasis and provide a therapeutic regimen for BC treatment.
