Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells
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-ph...
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creator | Aurora, Arin B. Khivansara, Vishal Leach, Ashley Gill, Jennifer G. Martin-Sandoval, Misty Yang, Chendong Kasitinon, Stacy Y. Bezwada, Divya Tasdogan, Alpaslan Gu, Wen Mathews, Thomas P. Zhao, Zhiyu DeBerardinis, Ralph J. Morrison, Sean J. |
description | 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 burdenwere 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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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 burdenwere 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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2120617119</identifier><identifier>PMID: 35110412</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Binding sites ; Biological Sciences ; Blood circulation ; Cancer ; Dehydrogenase ; Dehydrogenases ; Depletion ; Enzymatic activity ; Enzyme activity ; Enzymes ; Glucose ; Glucose 6 phosphate dehydrogenase ; Glucosephosphate dehydrogenase ; Glucosephosphate Dehydrogenase - metabolism ; Glutaminase ; Glutamine ; Glutamine - metabolism ; Glutathione ; Humans ; Intermediates ; Malic enzyme ; Melanoma ; Melanoma - metabolism ; Metastases ; Metastasis ; Mice ; Mice, Inbred NOD ; Mutants ; NADP - metabolism ; Oxidation resistance ; Oxidation-Reduction ; Oxidative stress ; Oxidative Stress - physiology ; Pentose ; Pentose phosphate pathway ; Pentose Phosphate Pathway - physiology ; Phosphates ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Substrates ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-02, Vol.119 (6), p.1-11</ispartof><rights>Copyright © 2022 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Feb 8, 2022</rights><rights>Copyright © 2022 the Author(s). Published by PNAS. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-239bcf971683f424149a8732a44ae118a769c81e9412272484f2c5ed82c394ce3</citedby><cites>FETCH-LOGICAL-c443t-239bcf971683f424149a8732a44ae118a769c81e9412272484f2c5ed82c394ce3</cites><orcidid>0000-0003-1587-8329</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833200/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833200/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35110412$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aurora, Arin B.</creatorcontrib><creatorcontrib>Khivansara, Vishal</creatorcontrib><creatorcontrib>Leach, Ashley</creatorcontrib><creatorcontrib>Gill, Jennifer G.</creatorcontrib><creatorcontrib>Martin-Sandoval, Misty</creatorcontrib><creatorcontrib>Yang, Chendong</creatorcontrib><creatorcontrib>Kasitinon, Stacy Y.</creatorcontrib><creatorcontrib>Bezwada, Divya</creatorcontrib><creatorcontrib>Tasdogan, Alpaslan</creatorcontrib><creatorcontrib>Gu, Wen</creatorcontrib><creatorcontrib>Mathews, Thomas P.</creatorcontrib><creatorcontrib>Zhao, Zhiyu</creatorcontrib><creatorcontrib>DeBerardinis, Ralph J.</creatorcontrib><creatorcontrib>Morrison, Sean J.</creatorcontrib><title>Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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 burdenwere 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.</description><subject>Animals</subject><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>Blood circulation</subject><subject>Cancer</subject><subject>Dehydrogenase</subject><subject>Dehydrogenases</subject><subject>Depletion</subject><subject>Enzymatic activity</subject><subject>Enzyme activity</subject><subject>Enzymes</subject><subject>Glucose</subject><subject>Glucose 6 phosphate dehydrogenase</subject><subject>Glucosephosphate dehydrogenase</subject><subject>Glucosephosphate Dehydrogenase - metabolism</subject><subject>Glutaminase</subject><subject>Glutamine</subject><subject>Glutamine - metabolism</subject><subject>Glutathione</subject><subject>Humans</subject><subject>Intermediates</subject><subject>Malic enzyme</subject><subject>Melanoma</subject><subject>Melanoma - metabolism</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mutants</subject><subject>NADP - metabolism</subject><subject>Oxidation resistance</subject><subject>Oxidation-Reduction</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - physiology</subject><subject>Pentose</subject><subject>Pentose phosphate pathway</subject><subject>Pentose Phosphate Pathway - physiology</subject><subject>Phosphates</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Substrates</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc2L1DAYxoMo7rh69qQUvHjpbt4kbZOLIItfMOBFzyGbvp3J0CY1SRfHk3-6KbOOHxAIyft7nuThIeQ50CugHb-evUlXDBhtoQNQD8gGqIK6FYo-JBtKWVdLwcQFeZLSgVKqGkkfkwveAFABbEN-bkNKVRiq3bjYkLBq63kf0rw3Gase98c-hh2WV7AaFm-zC75y3kYsN0X33fUmuzusUo5YjIzvV6dsJufDeEwuFbqaMJtUlvvh_K6cRuPDZCqL45iekkeDGRM-u98vydf3777cfKy3nz98unm7ra0QPNeMq1s7qA5ayYeSCIQysuPMCGEQQJquVVYCqpKKdUxIMTDbYC-Z5UpY5Jfkzcl3Xm4n7C36HM2o5-gmE486GKf_nXi317twp6XknFFaDF7fG8TwbcGU9eTSGsF4DEvSrGUNa5RqVUFf_YcewhJ9ibdSkjMJ0BXq-kTZWDqIOJw_A1Sv7eq1Xf2n3aJ4-XeGM_-7zgK8OAGHlEM8z1lRywYE_wWrSq0l</recordid><startdate>20220208</startdate><enddate>20220208</enddate><creator>Aurora, Arin B.</creator><creator>Khivansara, Vishal</creator><creator>Leach, Ashley</creator><creator>Gill, Jennifer G.</creator><creator>Martin-Sandoval, Misty</creator><creator>Yang, Chendong</creator><creator>Kasitinon, Stacy Y.</creator><creator>Bezwada, Divya</creator><creator>Tasdogan, Alpaslan</creator><creator>Gu, Wen</creator><creator>Mathews, Thomas P.</creator><creator>Zhao, Zhiyu</creator><creator>DeBerardinis, Ralph J.</creator><creator>Morrison, Sean J.</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1587-8329</orcidid></search><sort><creationdate>20220208</creationdate><title>Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells</title><author>Aurora, Arin B. ; Khivansara, Vishal ; Leach, Ashley ; Gill, Jennifer G. ; Martin-Sandoval, Misty ; Yang, Chendong ; Kasitinon, Stacy Y. ; Bezwada, Divya ; Tasdogan, Alpaslan ; Gu, Wen ; Mathews, Thomas P. ; Zhao, Zhiyu ; DeBerardinis, Ralph J. ; Morrison, Sean J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-239bcf971683f424149a8732a44ae118a769c81e9412272484f2c5ed82c394ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Binding sites</topic><topic>Biological Sciences</topic><topic>Blood circulation</topic><topic>Cancer</topic><topic>Dehydrogenase</topic><topic>Dehydrogenases</topic><topic>Depletion</topic><topic>Enzymatic activity</topic><topic>Enzyme activity</topic><topic>Enzymes</topic><topic>Glucose</topic><topic>Glucose 6 phosphate dehydrogenase</topic><topic>Glucosephosphate dehydrogenase</topic><topic>Glucosephosphate Dehydrogenase - 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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 burdenwere 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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>35110412</pmid><doi>10.1073/pnas.2120617119</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-1587-8329</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Binding sites Biological Sciences Blood circulation Cancer Dehydrogenase Dehydrogenases Depletion Enzymatic activity Enzyme activity Enzymes Glucose Glucose 6 phosphate dehydrogenase Glucosephosphate dehydrogenase Glucosephosphate Dehydrogenase - metabolism Glutaminase Glutamine Glutamine - metabolism Glutathione Humans Intermediates Malic enzyme Melanoma Melanoma - metabolism Metastases Metastasis Mice Mice, Inbred NOD Mutants NADP - metabolism Oxidation resistance Oxidation-Reduction Oxidative stress Oxidative Stress - physiology Pentose Pentose phosphate pathway Pentose Phosphate Pathway - physiology Phosphates Reactive oxygen species Reactive Oxygen Species - metabolism Substrates Tumors |
title | Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells |
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