Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA.
Mol Syst Biol. 2014 May 5;10(5):728. doi: 10.1002/msb.20134892.
Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients' microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low-invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.
谷氨酰胺在多种癌症的细胞生长中起着关键作用。依赖谷氨酰胺的癌细胞依赖谷氨酰胺才能存活，它们的代谢通过三羧酸（TCA）循环被重新编程以利用谷氨酰胺。在这里，我们发现了癌症侵袭性和谷氨酰胺依赖性之间缺失的一环。我们使用同位素示踪和生物能量分析发现，低侵袭性卵巢癌（OVCA）细胞不依赖谷氨酰胺，而高侵袭性 OVCA 细胞则明显依赖谷氨酰胺。与我们的发现一致，OVCA 患者的微阵列数据表明，谷氨酰胺分解与预后不良相关。值得注意的是，谷氨酰胺合成与分解相关基因表达的比值已成为患者预后的新型生物标志物。重要的是，我们发现谷氨酰胺调节 STAT3 的激活，STAT3 是信号通路的介导物，可调节高侵袭性 OVCA 细胞中的癌症特征。我们的研究结果表明，通过阻断谷氨酰胺进入 TCA 循环来靶向高侵袭性 OVCA 细胞，以及通过抑制谷氨酰胺合成和 STAT3 来靶向低侵袭性 OVCA 细胞的联合方法可能为治疗 OVCAs 提供潜在的治疗方法。
