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Article: Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival

TitleTargeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival
Authors
Keywordsaspartate
ATF4
LDHA
mTORC1
Warburg
Issue Date2018
Citation
EMBO Journal, 2018, v. 37, n. 20, article no. e99735 How to Cite?
AbstractNutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth. Reduced intracellular serine and aspartate following LDHA inhibition engage GCN2-ATF4 signaling to initiate an expansive pro-survival response. This includes the upregulation of glutamine transporter SLC1A5 and glutamine uptake, with concomitant build-up of essential amino acids, and mTORC1 activation, to ameliorate the effects of LDHA inhibition. Tumors with low LDHA expression and melanoma patients acquiring resistance to MAPK signaling inhibitors, which target the Warburg effect, exhibit altered metabolic gene expression reminiscent of the ATF4-mediated survival signaling. ATF4-controlled survival mechanisms conferring synthetic vulnerability to the approaches targeting the Warburg effect offer efficacious therapeutic strategies.
Persistent Identifierhttp://hdl.handle.net/10722/318730
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 5.489
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorPathria, Gaurav-
dc.contributor.authorScott, David A.-
dc.contributor.authorFeng, Yongmei-
dc.contributor.authorSang Lee, Joo-
dc.contributor.authorFujita, Yu-
dc.contributor.authorZhang, Gao-
dc.contributor.authorSahu, Avinash D.-
dc.contributor.authorRuppin, Eytan-
dc.contributor.authorHerlyn, Meenhard-
dc.contributor.authorOsterman, Andrei L.-
dc.contributor.authorRonai, Ze'ev A.-
dc.date.accessioned2022-10-11T12:24:25Z-
dc.date.available2022-10-11T12:24:25Z-
dc.date.issued2018-
dc.identifier.citationEMBO Journal, 2018, v. 37, n. 20, article no. e99735-
dc.identifier.issn0261-4189-
dc.identifier.urihttp://hdl.handle.net/10722/318730-
dc.description.abstractNutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth. Reduced intracellular serine and aspartate following LDHA inhibition engage GCN2-ATF4 signaling to initiate an expansive pro-survival response. This includes the upregulation of glutamine transporter SLC1A5 and glutamine uptake, with concomitant build-up of essential amino acids, and mTORC1 activation, to ameliorate the effects of LDHA inhibition. Tumors with low LDHA expression and melanoma patients acquiring resistance to MAPK signaling inhibitors, which target the Warburg effect, exhibit altered metabolic gene expression reminiscent of the ATF4-mediated survival signaling. ATF4-controlled survival mechanisms conferring synthetic vulnerability to the approaches targeting the Warburg effect offer efficacious therapeutic strategies.-
dc.languageeng-
dc.relation.ispartofEMBO Journal-
dc.subjectaspartate-
dc.subjectATF4-
dc.subjectLDHA-
dc.subjectmTORC1-
dc.subjectWarburg-
dc.titleTargeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.15252/embj.201899735-
dc.identifier.pmid30209241-
dc.identifier.scopuseid_2-s2.0-85053394018-
dc.identifier.volume37-
dc.identifier.issue20-
dc.identifier.spagearticle no. e99735-
dc.identifier.epagearticle no. e99735-
dc.identifier.eissn1460-2075-
dc.identifier.isiWOS:000447311200009-

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