PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

Molecular Oncology

Zhigang Zhu¹  Yin Zhu¹  Paul Yao²  Hongyu Zhang²  Jia Feng²  Qi Chen²  Ling Li³  Yang Lv³  Wei Xiang³  Ying Sun³  Rong Zhao⁴  Xiaodong Huang⁴  Min Li⁴  Weiguo Xie⁴ 

[1] Department of Geriatrics National Key Clinical Specialty Guangzhou First People's Hospital Guangzhou Medical University China;Department of Hematology Peking University Shenzhen Hospital China;Department of Pediatrics Hainan Maternal and Child Health Hospital Haikou China;Institute of Rehabilitation Center Tongren Hospital of Wuhan University China;

关键词: glycolysis;    lactate dehydrogenase;    LDHA;    mitochondria;    multiple myeloma;    PGC1β;   

DOI  :  10.1002/1878-0261.12363

来源: DOAJ

【 摘 要 】

Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1β and LDHA. In this study, we investigated the mechanism behind PGC1β‐mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real‐time PCR and western blotting were first used to evaluate gene expression of PGC1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1β or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1β or LDHA expression on tumor growth and mouse survival. We found that PGC1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1β through the PGC1β/RXRβ axis acting on the LDHA promoter. Overexpression of PGC1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1β or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Targeting the PGC1β/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.

【 授权许可】

Unknown