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PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress

DC Field Value Language
dc.contributor.author김재우-
dc.contributor.author윤보경-
dc.contributor.author정재호-
dc.contributor.author황성순-
dc.date.accessioned2023-07-12T03:00:10Z-
dc.date.available2023-07-12T03:00:10Z-
dc.date.issued2023-05-
dc.identifier.issn0027-8424-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/195467-
dc.description.abstractMolecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition. We show that under glutamine starvation, SEM-type GC cells up-regulate the 3 phosphoglycerate dehydrogenase (PHGDH)-mediated mitochondrial folate cycle pathway to produce NADPH as a reactive oxygen species scavenger for survival. This metabolic plasticity is associated with globally open chromatin structure in SEM-type GC cells, with ATF4/CEBPB identified as transcriptional drivers of the PHGDH-driven salvage pathway. Single-nucleus transcriptome analysis of patient-derived SEM-type GC organoids revealed intratumoral heterogeneity, with stemness-high subpopulations displaying high GLS expression, a resistance to GLS inhibition, and ATF4/CEBPB activation. Notably, coinhibition of GLS and PHGDH successfully eliminated stemness-high cancer cells. Together, these results provide insight into the metabolic plasticity of aggressive GC cells and suggest a treatment strategy for chemoresistant GC patients.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherNational Academy of Sciences-
dc.relation.isPartOfPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHGlutamine / metabolism-
dc.subject.MESHHumans-
dc.subject.MESHNutrients-
dc.subject.MESHPhosphoglycerate Dehydrogenase* / genetics-
dc.subject.MESHPhosphoglycerate Dehydrogenase* / metabolism-
dc.subject.MESHStomach Neoplasms* / drug therapy-
dc.subject.MESHStomach Neoplasms* / genetics-
dc.titlePHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Biochemistry and Molecular Biology (생화학-분자생물학교실)-
dc.contributor.googleauthorBo Kyung Yoon-
dc.contributor.googleauthorHyeonhui Kim-
dc.contributor.googleauthorTae Gyu Oh-
dc.contributor.googleauthorSe Kyu Oh-
dc.contributor.googleauthorSugyeong Jo-
dc.contributor.googleauthorMinki Kim-
dc.contributor.googleauthorKyu-Hye Chun-
dc.contributor.googleauthorNahee Hwang-
dc.contributor.googleauthorSuji Lee-
dc.contributor.googleauthorSuyon Jin-
dc.contributor.googleauthorAnnette R Atkins-
dc.contributor.googleauthorRuth T Yu-
dc.contributor.googleauthorMichael Downes-
dc.contributor.googleauthorJae-Woo Kim-
dc.contributor.googleauthorHyunkyung Kim-
dc.contributor.googleauthorRonald M Evans-
dc.contributor.googleauthorJae-Ho Cheong-
dc.contributor.googleauthorSungsoon Fang-
dc.identifier.doi10.1073/pnas.2217826120-
dc.contributor.localIdA00865-
dc.contributor.localIdA05928-
dc.contributor.localIdA03717-
dc.contributor.localIdA05443-
dc.relation.journalcodeJ02550-
dc.identifier.eissn1091-6490-
dc.identifier.pmid37192160-
dc.identifier.urlhttps://www.pnas.org/doi/10.1073/pnas.2217826120-
dc.subject.keyword3 phosphoglycerate dehydrogenase-
dc.subject.keywordgastric cancer-
dc.subject.keywordglutaminase-
dc.subject.keywordmetabolic plasticity-
dc.contributor.alternativeNameKim, Jae Woo-
dc.contributor.affiliatedAuthor김재우-
dc.contributor.affiliatedAuthor윤보경-
dc.contributor.affiliatedAuthor정재호-
dc.contributor.affiliatedAuthor황성순-
dc.citation.volume120-
dc.citation.number21-
dc.citation.startPagee2217826120-
dc.identifier.bibliographicCitationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.120(21) : e2217826120, 2023-05-
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers

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