| Title | PGC1 beta regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism |
| Authors | 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 |
| Affiliation | Peking Univ, Shenzhen Hosp, Dept Hematol, Shenzhen 518036, Peoples R China. Hainan Maternal & Child Hlth Hosp, Dept Pediat, Haikou 570206, Hainan, Peoples R China. Wuhan Univ, Tongren Hosp, Inst Rehabil Ctr, Wuhan 430060, Hubei, Peoples R China. Guangzhou Med Univ, Guangzhou Peoples Hosp 1, Dept Geriatr, Natl Key Clin Specialty, Guangzhou, Guangdong, Peoples R China. Peking Univ, Shenzhen Hosp, Dept Hematol, Shenzhen 518036, Peoples R China. Xiang, W (reprint author), Hainan Maternal & Child Hlth Hosp, Dept Pediat, Haikou 570206, Hainan, Peoples R China. Xie, WG (reprint author), Wuhan Univ, Tongren Hosp, Inst Rehabil Ctr, Wuhan 430060, Hubei, Peoples R China. |
| Keywords | glycolysis lactate dehydrogenase LDHA mitochondria multiple myeloma PGC1 beta MITOCHONDRIAL BIOGENESIS THERAPEUTIC TARGET GENE-EXPRESSION BREAST-CANCER ERR-ALPHA PGC-1-BETA CELLS INHIBITION RESISTANCE TUMORIGENESIS |
| Issue Date | 2018 |
| Publisher | MOLECULAR ONCOLOGY |
| Citation | MOLECULAR ONCOLOGY. 2018, 12(9), 1579-1595. |
| 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 beta and LDHA. In this study, we investigated the mechanism behind PGC1 beta-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 beta 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 beta-induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1 beta or LDHA lentivirus were established to evaluate invitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, invivo xenograft tumor development studies were performed to investigate the effect of PGC1 beta or LDHA expression on tumor growth and mouse survival. We found that PGC1 beta and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1 beta through the PGC1 beta/RXR beta axis acting on the LDHA promoter. Overexpression of PGC1 beta or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1 beta 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 beta-mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1 beta regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism. Targeting the PGC1 beta/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment. |
| URI | http://hdl.handle.net/20.500.11897/517558 |
| ISSN | 1878-0261 |
| DOI | 10.1002/1878-0261.12363 |
| Indexed | SCI(E) PubMed Medline |
| Appears in Collections: | 深圳医院 |
