Open AccessPGC 1β regulates multiple myeloma tumor growth through LDHA ‐mediated glycolytic metabolism
Author(s) -
Zhang Hongyu,
Li Ling,
Chen Qi,
Li Min,
Feng Jia,
Sun Ying,
Zhao Rong,
Zhu Yin,
Lv Yang,
Zhu Zhigang,
Huang Xiaodong,
Xie Weiguo,
Xiang Wei,
Yao Paul
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12363
Subject(s) - lactate dehydrogenase a , gene knockdown , cell growth , downregulation and upregulation , glycolysis , cancer research , carcinogenesis , biology , warburg effect , microbiology and biotechnology , apoptosis , cancer , biochemistry , metabolism , genetics , gene
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 PGC 1β and LDHA . In this study, we investigated the mechanism behind PGC 1β‐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 PGC 1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and si RNA techniques were used to investigate the mechanism underlying PGC 1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC 1β 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 PGC 1β or LDHA expression on tumor growth and mouse survival. We found that PGC 1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC 1β through the PGC 1β/ RXR β axis acting on the LDHA promoter. Overexpression of PGC 1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC 1β 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 PGC 1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC 1β regulates multiple myeloma tumor growth through LDHA ‐mediated glycolytic metabolism. Targeting the PGC 1β/ LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.