Marsico Michela, Santarsiero Anna, Pappalardo Ilaria, Convertini Paolo, Chiummiento Lucia, Sardone Alessandra, Di Noia Maria Antonietta, Infantino Vittoria, Todisco Simona
Department of Science, University of Basilicata, Viale dell'Ateneo lucano 10, 85100 Potenza, Italy.
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy.
Biomedicines. 2021 Nov 11;9(11):1664. doi: 10.3390/biomedicines9111664.
Metabolic reprogramming is a hallmark of cancer cells required to ensure high energy needs and the maintenance of redox balance. A relevant metabolic change of cancer cell bioenergetics is the increase in glutamine metabolism. Hepatocellular carcinoma (HCC), one of the most lethal cancer and which requires the continuous development of new therapeutic strategies, shows an up-regulation of human glutamate dehydrogenase 1 (hGDH1). GDH1 function may be relevant in cancer cells (or HCC) to drive the glutamine catabolism from L-glutamate towards the synthesis of α-ketoglutarate (α-KG), thus supplying key tricarboxylic acid cycle (TCA cycle) metabolites. Here, the effects of h gene silencing (si) and GDH1 inhibition were evaluated. Our results demonstrate that si in HepG2 cells induces a significant reduction in cell proliferation (58.8% ± 10.63%), a decrease in BCL2 expression levels, mitochondrial mass (75% ± 5.89%), mitochondrial membrane potential (30% ± 7.06%), and a significant increase in mitochondrial superoxide anion (25% ± 6.55%) compared to control/untreated cells. The inhibition strategy leads us to identify two possible inhibitors of hGDH1: quercetin and Permethylated Anigopreissin A (PAA). These findings suggest that hGDH1 could be a potential candidate target to impair the metabolic reprogramming of HCC cells.
代谢重编程是癌细胞的一个标志，对于确保高能量需求和维持氧化还原平衡至关重要。癌细胞生物能量学的一个相关代谢变化是谷氨酰胺代谢增加。肝细胞癌（HCC）是最致命的癌症之一，需要不断开发新的治疗策略，其显示人谷氨酸脱氢酶1（hGDH1）上调。GDH1的功能可能与癌细胞（或HCC）中驱动谷氨酰胺从L-谷氨酸分解代谢为α-酮戊二酸（α-KG）的过程相关，从而提供关键的三羧酸循环（TCA循环）代谢物。在此，评估了h基因沉默（si）和GDH1抑制的效果。我们的结果表明，与对照/未处理细胞相比，HepG2细胞中的si诱导细胞增殖显著降低（58.8%±10.63%），BCL2表达水平、线粒体质量（75%±5.89%）、线粒体膜电位（30%±7.06%）降低，线粒体超氧阴离子显著增加（25%±6.55%）。抑制策略使我们鉴定出两种可能的hGDH1抑制剂：槲皮素和全甲基化的Anigopreissin A（PAA）。这些发现表明，hGDH1可能是损害HCC细胞代谢重编程的潜在候选靶点。
