Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells.
Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells.
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DOI：
10.1073/pnas.2120617119
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发表时间：
2022-02-08
影响因子：
11.1
通讯作者：
Morrison SJ
中科院分区：
文献类型：
--
作者：
Aurora AB;Khivansara V;Leach A;Gill JG;Martin-Sandoval M;Yang C;Kasitinon SY;Bezwada D;Tasdogan A;Gu W;Mathews TP;Zhao Z;DeBerardinis RJ;Morrison SJ
黑色素瘤转移受氧化应激的限制。进入血液的细胞经历高水平的活性氧，通常死于铁凋亡。我们发现，黑色素瘤细胞变得更加依赖于氧化戊糖磷酸途径来管理转移过程中的氧化应激。当戊糖磷酸途径功能受损，减少葡萄糖6-磷酸脱氢酶（G6 PD）的功能，黑色素瘤细胞增加苹果酸酶的活性和谷氨酰胺的消耗。因此，黑色素瘤细胞对氧化应激具有冗余和分层的保护。磷酸戊糖途径是癌细胞抗氧化应激的主要来源，但当一些癌细胞经历高水平的氧化应激时，对其在转移中的作用的了解有限。为了解决这个问题，我们突变了葡萄糖6-磷酸脱氢酶（G6 PD）的底物结合位点，该位点催化患者来源的黑色素瘤中戊糖磷酸途径的第一步。G6 PD突变型黑色素瘤显著降低了G6 PD酶活性，并消耗了氧化戊糖磷酸途径中的中间产物。G6 PD功能降低对原发性皮下肿瘤的形成几乎没有影响，但当这些肿瘤自发转移时，血液中循环黑色素瘤细胞的频率和转移性疾病负担显著降低。与对照黑色素瘤相比，G6 PD突变型黑色素瘤表现出活性氧水平升高、NADPH水平降低和谷胱甘肽耗尽。G6 PD突变型黑色素瘤通过增加苹果酸酶活性和谷氨酰胺消耗来补偿氧化应激的增加。这产生了一种新的代谢脆弱性，因为G6 PD突变型黑色素瘤比对照黑色素瘤更依赖于转氨酶，无论是氧化应激管理还是回补。因此，氧化戊糖磷酸途径、苹果酸酶和β-氨基糖苷酶在转移过程中提供了针对氧化应激的分层保护。
Melanoma metastasis is limited by oxidative stress. Cells that enter the blood experience high levels of reactive oxygen species and usually die of ferroptosis. We found that melanoma cells become more dependent upon the oxidative pentose phosphate pathway to manage oxidative stress during metastasis. When pentose phosphate pathway function was impaired by reduced glucose 6-phosphate dehydrogenase (G6PD) function, melanoma cells increased malic enzyme activity and glutamine consumption. Melanoma cells thus have redundant and layered protection against oxidative stress. The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there is limited insight into its role in metastasis, when some cancer cells experience high levels of oxidative stress. To address this, we mutated the substrate binding site of glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, in patient-derived melanomas. G6PD mutant melanomas had significantly decreased G6PD enzymatic activity and depletion of intermediates in the oxidative pentose phosphate pathway. Reduced G6PD function had little effect on the formation of primary subcutaneous tumors, but when these tumors spontaneously metastasized, the frequency of circulating melanoma cells in the blood and metastatic disease burden were significantly reduced. G6PD mutant melanomas exhibited increased levels of reactive oxygen species, decreased NADPH levels, and depleted glutathione as compared to control melanomas. G6PD mutant melanomas compensated for this increase in oxidative stress by increasing malic enzyme activity and glutamine consumption. This generated a new metabolic vulnerability as G6PD mutant melanomas were more dependent upon glutaminase than control melanomas, both for oxidative stress management and anaplerosis. The oxidative pentose phosphate pathway, malic enzyme, and glutaminolysis thus confer layered protection against oxidative stress during metastasis.
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影响因子：
5.6
作者：
Gómez-Manzo S;Marcial-Quino J;Vanoye-Carlo A;Serrano-Posada H;Ortega-Cuellar D;González-Valdez A;Castillo-Rodríguez RA;Hernández-Ochoa B;Sierra-Palacios E;Rodríguez-Bustamante E;Arreguin-Espinosa R
通讯作者：
Arreguin-Espinosa R
影响因子：
20.8
作者：
Chen, Li;Zhang, Zhaoyue;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.
影响因子：
13.6
作者：
Ding H;Chen Z;Wu K;Huang SM;Wu WL;LeBoeuf SE;Pillai RG;Rabinowitz JD;Papagiannakopoulos T
通讯作者：
Papagiannakopoulos T
影响因子：
5.7
作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
通讯作者：
Bennett, Mark K.
影响因子：
4.8
作者：
Brosnan, JT;Brosnan, ME;Nissim, I
通讯作者：
Nissim, I