Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer.
Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer.
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DOI：
10.1002/msb.20134892
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发表时间：
2014-05-05
影响因子：
9.9
通讯作者：
Nagrath, Deepak
中科院分区：
文献类型：
--
作者：
Yang, Lifeng;Moss, Tyler;Mangala, Lingegowda S.;Marini, Juan;Zhao, Hongyun;Wahlig, Stephen;Armaiz-Pena, Guillermo;Jiang, Dahai;Achreja, Abhinav;Win, Julia;Roopaimoole, Rajesha;Rodriguez-Aguayo, Cristian;Mercado-Uribe, Imelda;Lopez-Berestein, Gabriel;Liu, Jinsong;Tsukamoto, Takashi;Sood, Anil K.;Ram, Prahlad T.;Nagrath, Deepak
谷氨酰胺可以在多种癌症的细胞生长中发挥关键作用。谷氨酰胺成瘾的癌细胞依赖谷氨酰胺维持生存，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之间缺失的联系。通过同位素示踪和生物能量分析，我们发现低侵袭性卵巢癌（OVCA）细胞是谷氨酰胺不依赖的，而高侵袭性OVCA细胞则明显依赖谷氨酰胺。与我们的研究结果一致，OVCA患者的微阵列数据表明谷氨酰胺溶解与较差的生存率相关。值得注意的是，与谷氨酰胺合成代谢与分解代谢相关的基因表达比例已成为患者预后的一种新的生物标志物。值得注意的是，我们发现谷氨酰胺调节STAT3的激活，STAT3是侵袭性OVCA细胞中调节癌症特征的信号通路的介质。我们的研究结果表明，通过阻断谷氨酰胺进入TCA循环靶向高侵袭性OVCA细胞，以及通过抑制谷氨酰胺合成和STAT3靶向低侵袭性OVCA细胞的联合方法可能导致治疗OVCA的潜在治疗方法。
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.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
3.7
作者：
Gough DJ;Koetz L;Levy DE
通讯作者：
Levy DE
影响因子：
9.9
作者：
Graham, Nicholas A.;Tahmasian, Martik;Kohli, Bitika;Komisopoulou, Evangelia;Zhu, Maggie;Vivanco, Igor;Teitell, Michael A.;Wu, Hong;Ribas, Antoni;Lo, Roger S.;Mellinghoff, Ingo K.;Mischel, Paul S.;Graeber, Thomas G.
通讯作者：
Graeber, Thomas G.
影响因子：
9.9
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
通讯作者：
Chiaradonna, Ferdinando
影响因子：
4.3
作者：
Dang, Chi V.
通讯作者：
Dang, Chi V.