Bagaloni Irene, Visani Axel, Biagiotti Sara, Ruzzo Annamaria, Navari Mohsen, Etebari Maryam, Mundo Lucia, Granai Massimo, Lazzi Stefano, Isidori Alessandro, Loscocco Federica, Li Jiejin, Leoncini Lorenzo, Visani Giuseppe, Magnani Mauro, Piccaluga Pier Paolo
Department of Biomolecular Sciences (DISB), University of Urbino, Urbino, Italy.
Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy.
Front Oncol. 2021 Sep 2;11:661102. doi: 10.3389/fonc.2021.661102. eCollection 2021.
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 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.
细胞能量代谢改变最近已成为肿瘤细胞的一个重要特征。事实上，干扰癌细胞代谢可能是一种合适的治疗策略。在本研究中，我们旨在评估人类淋巴瘤中的葡萄糖代谢激活情况，并评估二甲双胍如何对淋巴瘤细胞发挥作用。我们研究了一大系列人类淋巴瘤（N = 252）以及伯基特淋巴瘤（BL）细胞的一个模型。我们结合了分子生物学技术，包括全基因表达谱（GEP）分析、定量聚合酶链反应（qPCR）和蛋白质免疫印迹法，以及生化检测，旨在评估磷酸戊糖途径、三羧酸（TCA）循环和有氧糖酵解速率。我们发现，基于基因表达谱（GEP），大多数淋巴瘤亚型的葡萄糖代谢总体上增强，普遍转向有氧糖酵解。相比之下，正常B细胞在生发中心转变过程中仅显示葡萄糖利用总体增加。有趣的是，不仅高度增殖的侵袭性淋巴瘤，而且惰性淋巴瘤，如边缘区淋巴瘤，也表现出这种现象。一致地，qPCR证实参与糖酵解的基因在BL细胞中过表达。生化检测表明，虽然有氧糖酵解增加，但TCA循环减少。最后，我们表明二甲双胍可以通过诱导葡萄糖转运蛋白1（GLUT1）、丙酮酸激酶M2（PKM2）和乳酸脱氢酶A（LDHA）来加重细胞代谢，从而诱导BL细胞死亡。总之，我们揭示了人类淋巴瘤中的葡萄糖代谢异常，并阐明了二甲双胍在伯基特淋巴瘤模型中的作用机制。
