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dc.contributor.author
Ozcan, Selahattin C.
dc.contributor.author
Mutlu, Aydan
dc.contributor.author
Altunok, Tugba H.
dc.contributor.author
Gurpinar, Yunus
dc.contributor.author
Sarioglu, Aybike
dc.contributor.author
Guler, Sabire
dc.contributor.author
Muchut, Robertino José
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dc.contributor.author
Iglesias, Alberto Alvaro
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dc.contributor.author
Celikler, Serap
dc.contributor.author
Campbell, Paul M.
dc.contributor.author
Yalcin, Abdullah
dc.date.available
2022-08-11T11:51:54Z
dc.date.issued
2021-09
dc.identifier.citation
Ozcan, Selahattin C.; Mutlu, Aydan; Altunok, Tugba H.; Gurpinar, Yunus; Sarioglu, Aybike; et al.; Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells; Academic Press Inc Elsevier Science; Biochemical and Biophysical Research Communications; 571; 9-2021; 118-124
dc.identifier.issn
0006-291X
dc.identifier.uri
http://hdl.handle.net/11336/165112
dc.description.abstract
Activating 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 KRAS-transformation 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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Academic Press Inc Elsevier Science
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dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
AZ PFKFB3 26
dc.subject
CB-839
dc.subject
GLS1
dc.subject
KRAS
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PANCREATIC DUCTAL ADENOCARCINOMA
dc.subject
PFKFB3
dc.subject.classification
Bioquímica y Biología Molecular
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2022-08-08T15:16:30Z
dc.journal.volume
571
dc.journal.pagination
118-124
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Ozcan, Selahattin C.. Koc University Research Center For Translational Medici; Turquía
dc.description.fil
Fil: Mutlu, Aydan. Bursa Uludag University; Turquía
dc.description.fil
Fil: Altunok, Tugba H.. Bursa Uludag University; Turquía
dc.description.fil
Fil: Gurpinar, Yunus. Bursa Uludag University; Turquía
dc.description.fil
Fil: Sarioglu, Aybike. Bursa Uludag University; Turquía
dc.description.fil
Fil: Guler, Sabire. Bursa Uludag University; Turquía
dc.description.fil
Fil: Muchut, Robertino José. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina
dc.description.fil
Fil: Iglesias, Alberto Alvaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral; Argentina
dc.description.fil
Fil: Celikler, Serap. Bursa Uludag University; Turquía
dc.description.fil
Fil: Campbell, Paul M.. The Marvin and Concetta Greenberg Pancreatic Cancer Institute; Estados Unidos
dc.description.fil
Fil: Yalcin, Abdullah. Bursa Uludag University; Turquía
dc.journal.title
Biochemical and Biophysical Research Communications
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0006291X21011062
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.bbrc.2021.07.070
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