Publication:
Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS transformed pancreatic cells

dc.contributor.authorÖzcan, Selahattin C.
dc.contributor.authorMutlu, Aydan
dc.contributor.authorAltunok, Tuğba H.
dc.contributor.authorGürpınar, Yunus
dc.contributor.authorSarıoğlu, Aybike
dc.contributor.authorGüler, Sabire
dc.contributor.authorMuchut, Robertino J.
dc.contributor.authorIglesias, Alberto A.
dc.contributor.authorÇelikler, Serap
dc.contributor.authorCampbell, Paul M.
dc.contributor.authorYalçın, Abdullah
dc.contributor.buuauthorGÜLER, SABİRE
dc.contributor.buuauthorÇELİKLER KASIMOĞULLARI, SERAP
dc.contributor.buuauthorYALÇIN, ABDULLAH
dc.contributor.buuauthorMutlu, Aydan
dc.contributor.buuauthorAltunok, Tuğba H.
dc.contributor.buuauthorSarıoğlu, Aybike
dc.contributor.orcid0000-0003-1263-3799
dc.contributor.orcid0000-0002-8287-6617
dc.contributor.orcid0000-0002-4177-3478
dc.contributor.orcid0000-0001-8519-8375
dc.contributor.researcheridFNG-9051-2022
dc.contributor.researcheridGCY-0775-2022
dc.contributor.researcheridS-2474-2018
dc.contributor.researcheridHTY-9355-2023
dc.contributor.researcheridJCD-5015-2023
dc.contributor.researcheridABI-4164-2020
dc.date.accessioned2024-06-03T10:38:27Z
dc.date.available2024-06-03T10:38:27Z
dc.date.issued2021-09-24
dc.description.abstractActivating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAStransformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth. (c) 2021 Published by Elsevier Inc.
dc.identifier.doi10.1016/j.bbrc.2021.07.070
dc.identifier.endpage124
dc.identifier.issn0006-291X
dc.identifier.issn1090-2104
dc.identifier.pubmed34325126
dc.identifier.startpage118
dc.identifier.urihttps://doi.org/10.1016/j.bbrc.2021.07.070
dc.identifier.urihttps://hdl.handle.net/11452/41665
dc.identifier.urihttps://www.sciencedirect.com/science/article/pii/S0006291X21011062
dc.identifier.volume571
dc.identifier.wos000678338900008
dc.indexed.pubmedPubMed
dc.indexed.wosWOS.SCI
dc.language.isoen
dc.publisherAcademic Press
dc.relation.bapDDP (F) 2018/3
dc.relation.journalBiochemical and Biophysical Research Communications
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi
dc.relation.tubitak114Z496
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectGrowth
dc.subjectBeta
dc.subjectPancreatic ductal adenocarcinoma
dc.subjectKras
dc.subjectGls1
dc.subjectCb-839
dc.subjectPfkfb3
dc.subjectAz pfkfb3 26
dc.subjectScience & technology
dc.subjectLife sciences & biomedicine
dc.subjectBiochemistry & molecular biology
dc.subjectBiochemistry & molecular biology
dc.subjectBiophysics
dc.titleSimultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS transformed pancreatic cells
dc.typeArticle
dspace.entity.typePublication
relation.isAuthorOfPublication65c482b5-8e65-438b-934f-90fef538a967
relation.isAuthorOfPublicationd293a689-5b5d-4b75-84b7-ae61987b866a
relation.isAuthorOfPublication24332407-6513-4c39-92c2-21a376f853b1
relation.isAuthorOfPublication.latestForDiscovery65c482b5-8e65-438b-934f-90fef538a967

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