Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells

Abstract

Significance 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.