Abstract
Altered cellular energetic metabolism has recently emerged as important feature of neoplastic cells. Indeed, interfering with cancer cell metabolism might represent a suitable therapeutic strategy. In this study, we aimed to assess glucose metabolism activation in human lymphomas and evaluate how metformin can exert its action on lymphoma cells. We studied a large series of human lymphomas (N = 252) and an in vitro model of Burkitt lymphoma (BL) cells. We combined molecular biology techniques, including global gene expression profiling (GEP) analysis, quantitative PCR (qPCR) and Western blotting, and biochemical assays, aimed to assess pentose phosphate pathway, tricarboxylic acid (TCA) cycle, and aerobic glycolysis rates. We found that glucose metabolism is overall enhanced in most lymphoma subtypes, based on gene expression profiling (GEP), with general shift to aerobic glycolysis. By contrast, normal B cells only showed an overall increase in glucose usage during germinal center transition. Interestingly, not only highly proliferating aggressive lymphomas but also indolent ones, like marginal zone lymphomas, showed the phenomenon. Consistently, genes involved in glycolysis were confirmed to be overexpressed in BL cells by qPCR. Biochemical assays showed that while aerobic glycolysis is increased, TCA cycle is reduced. Finally, we showed that metformin can induce cell death in BL cells by stressing cellular metabolism through the induction of GLUT1, PKM2, and LDHA. In conclusion, we unveiled glucose metabolism abnormalities in human lymphomas and characterized the mechanism of action of metformin in Burkitt lymphoma model.
Highlights
Altered cellular energetic metabolism is emerging as one of the most important hallmarks of malignantly transformed cells
Two hundred fifty-two B-cell-derived malignancies and 25 samples of normal B-cell subpopulations were studied by gene expression profiling (GEP) analysis, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma, not otherwise specified (DLBCL/NOS), primary mediastinal large Bcell lymphoma (PMBCL), Burkitt lymphoma (BL), splenic marginal zone lymphoma (SMZL), plasma cell myeloma (PCM), classical Hodgkin lymphoma, and lymphocytepredominant Hodgkin lymphoma (NLPHL) and normal Bcell subpopulations including centroblasts (CB), centrocytes (CC), naive (N), memory cells (M), and plasma cells (PC) [20,21,22,23]
To validate the results observed in the gene sets from microarray data, which reported the upregulation of genes involved in glucose metabolism in patients affected with BL, we investigated the gene expression of six selected genes involved in glucose metabolism in both DAUDI and Peripheral blood lymphocytes (PBL) by means of RT-quantitative PCR (qPCR)
Summary
Altered cellular energetic metabolism is emerging as one of the most important hallmarks of malignantly transformed cells. Tumor cells are subjected to several changes in metabolic pathways, among which the shift from oxidative phosphorylation to lactate fermentation, known as Warburg effect, plays a key role. Normal cells convert glucose into carbonic anhydride under aerobic conditions through oxidative phosphorylation. Cancer cells mainly produce lactate, even in the presence of sufficient levels of oxygen [1]. Aerobic glycolysis is less efficient in producing energy (2 ATP molecules instead of 36 from complete glucose oxidation), this apparent waste of glucose really constitutes a survival advantage in active proliferating cells because it makes them insensitive to transient or permanent hypoxic conditions. Lactate is not just a waste product of the process; it promotes tumor invasion supporting cell migration, angiogenesis, immune escape, and radioresistance [2]. The Warburg effect is still extremely relevant in the cancer research field because understanding the complex cancer energy metabolism will help to develop new approaches in early diagnosis and cancer therapy
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