Caneba C A, Yang L, Baddour J, Curtis R, Win J, Hartig S, Marini J, Nagrath D
1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Bioengineering, Rice University, Houston, TX, USA.
1] Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA [2] Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
Cell Death Dis. 2014 Jun 26;5(6):e1302. doi: 10.1038/cddis.2014.264.
Ovarian cancer (OVCA) is among the most lethal gynecological cancers leading to high mortality rates among women. Increasing evidence indicate that cancer cells undergo metabolic transformation during tumorigenesis and growth through nutrients and growth factors available in tumor microenvironment. This altered metabolic rewiring further enhances tumor progression. Recent studies have begun to unravel the role of amino acids in the tumor microenvironment on the proliferation of cancer cells. One critically important, yet often overlooked, component to tumor growth is the metabolic reprogramming of nitric oxide (NO) pathways in cancer cells. Multiple lines of evidence support the link between NO and tumor growth in some cancers, including pancreas, breast and ovarian. However, the multifaceted role of NO in the metabolism of OVCA is unclear and direct demonstration of NO's role in modulating OVCA cells' metabolism is lacking. This study aims at indentifying the mechanistic links between NO and OVCA metabolism. We uncover a role of NO in modulating OVCA metabolism: NO positively regulates the Warburg effect, which postulates increased glycolysis along with reduced mitochondrial activity under aerobic conditions in cancer cells. Through both NO synthesis inhibition (using L-arginine deprivation, arginine is a substrate for NO synthase (NOS), which catalyzes NO synthesis; using L-Name, a NOS inhibitor) and NO donor (using DETA-NONOate) analysis, we show that NO not only positively regulates tumor growth but also inhibits mitochondrial respiration in OVCA cells, shifting these cells towards glycolysis to maintain their ATP production. Additionally, NO led to an increase in TCA cycle flux and glutaminolysis, suggesting that NO decreases ROS levels by increasing NADPH and glutathione levels. Our results place NO as a central player in the metabolism of OVCA cells. Understanding the effects of NO on cancer cell metabolism can lead to the development of NO targeting drugs for OVCAs.
卵巢癌（OVCA）是最致命的妇科癌症之一，导致女性死亡率居高不下。越来越多的证据表明，癌细胞在肿瘤发生和生长过程中通过肿瘤微环境中可用的营养物质和生长因子进行代谢转变。这种改变的代谢重排进一步促进肿瘤进展。最近的研究开始揭示肿瘤微环境中氨基酸对癌细胞增殖的作用。肿瘤生长的一个至关重要但经常被忽视的组成部分是癌细胞中一氧化氮（NO）途径的代谢重编程。多条证据支持NO与包括胰腺、乳腺和卵巢在内的某些癌症中的肿瘤生长之间的联系。然而，NO在OVCA代谢中的多方面作用尚不清楚，并且缺乏NO在调节OVCA细胞代谢中作用的直接证据。本研究旨在确定NO与OVCA代谢之间的机制联系。我们发现NO在调节OVCA代谢中的作用：NO正向调节瓦伯格效应，该效应假定在有氧条件下癌细胞中糖酵解增加而线粒体活性降低。通过NO合成抑制（使用L - 精氨酸剥夺，精氨酸是一氧化氮合酶（NOS）的底物，NOS催化NO合成；使用NOS抑制剂L - 硝基精氨酸甲酯）和NO供体（使用二乙三胺 NONOate）分析，我们表明NO不仅正向调节肿瘤生长，还抑制OVCA细胞中的线粒体呼吸，使这些细胞转向糖酵解以维持其ATP产生。此外，NO导致三羧酸循环通量和谷氨酰胺分解增加，表明NO通过增加NADPH和谷胱甘肽水平来降低ROS水平。我们的结果表明NO是OVCA细胞代谢的核心参与者。了解NO对癌细胞代谢的影响可导致开发针对OVCA的NO靶向药物。
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