2. Academic Validation
  3. The tumor suppressor Parkin exerts anticancer effects through regulating mitochondrial GAPDH activity

The tumor suppressor Parkin exerts anticancer effects through regulating mitochondrial GAPDH activity

  • Oncogene. 2024 Oct;43(44):3215-3226. doi: 10.1038/s41388-024-03157-3.
Xin Sun 1,  Guiqin Ye 2,  Jiuzhou Li 3,  Liyang Yuan 4,  Gongxun Bai 5,  Yong-Jiang Xu 6,  Jianbin Zhang 7
Affiliations

Affiliations

  • 1 Cancer Center, Department of Medical Oncology, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
  • 2 Department of Clinical Laboratory, Yuhuan People's Hospital, Taizhou, China.
  • 3 Department of Neurosurgery, Binzhou People's Hospital, Binzhou, China.
  • 4 State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Jiangnan University, Wuxi, China.
  • 5 College of Optical and Electronic Technology, China Jiliang University, Hangzhou, China. baigx@cjlu.edu.cn.
  • 6 State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Jiangnan University, Wuxi, China. yjxutju@gmail.com.
  • 7 Cancer Center, Department of Medical Oncology, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China. zhangjianbin@hmc.edu.cn.
PMID: 39285229 DOI: 10.1038/s41388-024-03157-3
Abstract

Cancer cells preferentially utilize glycolysis for energy production, and GAPDH is a critical Enzyme in glycolysis. Parkin is a tumor suppressor and a key protein involved in Mitophagy regulation. However, the tumor suppression mechanism of Parkin has still not been elucidated. In this study, we identified mitochondrial GAPDH as a new substrate of the E3 ubiquitin Ligase Parkin, which mediated GAPDH ubiquitination in human cervical Cancer. The translocation of GAPDH into mitochondria was driven by the PINK1 kinase, and either PINK1 or GAPDH mutation prevented the accumulation of GAPDH in mitochondria. Parkin caused the ubiquitination of GAPDH at multiple sites (K186, K215, and K219) located within the enzyme-catalyzed binding domain of the GAPDH protein. GAPDH ubiquitination was required for Mitophagy, and stimulation of Mitophagy suppressed cervical Cancer cell growth, indicating that Mitophagy serves as a type of cell death. Mechanistically, PHB2 served as a key mediator in GAPDH ubiquitination-induced Mitophagy through stabilizing PINK1 protein and GAPDH mutation resulted in the reduced distribution of PHB2 in mitophagic vacuole. In addition, ubiquitination of GAPDH decreased its phosphorylation level and Enzyme activity and inhibited the glycolytic pathway in cervical Cancer cells. The results of in vivo experiments also showed that the GAPDH mutation increased glycolysis in cervical Cancer cells and accelerated tumorigenesis. Thus, we concluded that Parkin may exert its Anticancer function by ubiquitinating GAPDH in mitochondria. Taken together, our study further clarified the molecular mechanism of tumor suppression by Parkin through the regulation of energy metabolism, which provides an experimental basis for the development of new drugs for the treatment of human cervical Cancer.

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