Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway.
Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway.
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DOI：
10.1530/erc-15-0192
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发表时间：
2015-08
影响因子：
3.9
通讯作者：
Bae-Jump VL
中科院分区：
文献类型：
--
作者：
Yuan L;Sheng X;Willson AK;Roque DR;Stine JE;Guo H;Jones HM;Zhou C;Bae-Jump VL
谷氨酰胺是肿瘤细胞用于生物合成的主要营养物质之一。因此，靶向抑制谷氨酰胺代谢可能具有抗肿瘤作用。在本研究中，我们的目的是评估谷氨酰胺对卵巢癌细胞生长的影响。通过分析细胞毒性、细胞周期进程、细胞凋亡、细胞应激和葡萄糖/谷氨酰胺代谢，测定了三种卵巢癌细胞系HEY、SKOV 3和IGT-1的谷氨酰胺依赖性。我们的研究结果表明，谷氨酰胺的管理增加细胞增殖在所有三个卵巢癌细胞系中的剂量依赖性的方式。谷氨酰胺耗竭诱导活性氧和内质网应激蛋白的表达。此外，谷氨酰胺通过调节mTOR/S6和MAPK途径增加谷氨酰胺酶（GLS）和谷氨酸脱氢酶（GDH）的活性。通过雷帕霉素抑制mTOR活性或通过siRNA阻断S6表达抑制GDH和GLS活性，导致谷氨酰胺诱导的细胞增殖减少。这些研究表明，针对谷氨酰胺代谢可能是一个有前途的治疗策略，在卵巢癌的治疗。
Glutamine is one of the main nutrients used by tumor cells for biosynthesis. Therefore, targeted inhibition of glutamine metabolism may have anti-tumorigenic implications. In the present study, we aimed to evaluate the effects of glutamine on ovarian cancer cell growth. Three ovarian cancer cell lines, HEY, SKOV3, and IGROV-1, were assayed for glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis, cell stress, and glucose/glutamine metabolism. Our results revealed that administration of glutamine increased cell proliferation in all three ovarian cancer cell lines in a dose dependent manner. Depletion of glutamine induced reactive oxygen species and expression of endoplasmic reticulum stress proteins. In addition, glutamine increased the activity of glutaminase (GLS) and glutamate dehydrogenase (GDH) by modulating the mTOR/S6 and MAPK pathways. Inhibition of mTOR activity by rapamycin or blocking S6 expression by siRNA inhibited GDH and GLS activity, leading to a decrease in glutamine-induced cell proliferation. These studies suggest that targeting glutamine metabolism may be a promising therapeutic strategy in the treatment of ovarian cancer.