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 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.
Highlights
Multiple myeloma (MM) is a hematologic malignancy characterized by antibody-secreting plasma cells with proliferation in abnormal bone marrow (Gong et al, 2016; Landgren and Morgan, 2014)
Isolated primary normal B lymphocytes (NBL), several multiple myeloma cells lines, including U266B1, RPMI8226, and MM.1R, and CD138+ were used for mRNA analysis. It showed that the mRNA expression for both peroxisome proliferator-activated receptor-c coactivator-1b (PGC1b) and LDH isoform A (LDHA) was significantly increased in MM cells compared to NBL cells, while there was no difference for LDHB and LDHC
We evaluated the potential role of PGC1b on the contribution of LDHA expression
Summary
Multiple myeloma (MM) is a hematologic malignancy characterized by antibody-secreting plasma cells with proliferation in abnormal bone marrow (Gong et al, 2016; Landgren and Morgan, 2014). The median overall survival rate has been significantly improved during the last decades due to advanced understanding of its molecular basis as well as development of novel therapies, including immune modulator agents, proteasome inhibitor drugs, and allogeneic stem cell transplantation (Sherbenou et al, 2016). Development of novel therapeutic approaches and targeting of abnormal cancer metabolism in molecular and cellular heterogeneity of MM may provide us with new strategies for overcoming this disease (Dalva-Aydemir et al, 2015; Dimopoulos et al, 2018; Naymagon and AbdulHay, 2016). LDH isoform A (LDHA) has been reported to be upregulated in many cancer cells (Bui and Thompson, 2006) and favors tumor invasion and metastasis by promoting the metabolic switch to glycolysis (Jin et al, 2017). LDHA is highly expressed in MM cell lines, and targeting LDHA is considered a novel therapeutic approach, while the potential mechanism for LDHA upregulation remains unclear (Fujiwara et al, 2013; Maiso et al, 2015)
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