期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：6
DOI：10.1073/pnas.2120617119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
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.
