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Artículo

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

Ozcan, Selahattin C.; Mutlu, Aydan; Altunok, Tugba H.; Gurpinar, Yunus; Sarioglu, Aybike; Guler, Sabire; Muchut, Robertino JoséIcon ; Iglesias, Alberto AlvaroIcon ; Celikler, Serap; Campbell, Paul M.; Yalcin, Abdullah
Fecha de publicación: 09/2021
Editorial: Academic Press Inc Elsevier Science
Revista: Biochemical and Biophysical Research Communications
ISSN: 0006-291X
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

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.
Palabras clave: AZ PFKFB3 26 , CB-839 , GLS1 , KRAS , PANCREATIC DUCTAL ADENOCARCINOMA , PFKFB3
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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/165112
URL: https://linkinghub.elsevier.com/retrieve/pii/S0006291X21011062
DOI: http://dx.doi.org/10.1016/j.bbrc.2021.07.070
Colecciones
Articulos(CCT - SANTA FE)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - SANTA FE
Citación
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
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