PGC1? regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism.

ABSTRACT: 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 PGC1? and LDHA. In this study, we investigated the mechanism behind PGC1?-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 PGC1? 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 PGC1?-induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1? 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 PGC1? or LDHA expression on tumor growth and mouse survival. We found that PGC1? and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1? through the PGC1?/RXR? axis acting on the LDHA promoter. Overexpression of PGC1? or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1? 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 PGC1?-mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1? regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism. Targeting the PGC1?/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.

SUBMITTER: Zhang H 

PROVIDER: S-EPMC6120252 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature