K-<i>ras</i> Codon-Specific Mutations Produce Distinctive Metabolic Phenotypes in Human Fibroblasts

Vizán, Pedro; Boros, László G.; Figueras, Agnés; Capellà, Gabriel; Mangues, Ramón; Bassilian, Sara; Lim, Shu; Lee, Wai‐Nang P.; Cascante, Marta

doi:10.1158/0008-5472.can-05-0074

Cited by 106 publications

(83 citation statements)

References 17 publications

(25 reference statements)

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“…Accordingly, if glycolytic flux is inadequate, then such diffusion limitations may restrict the availability of energy and anabolic precursors, which then may hinder spheroid or tumor growth. Regardless, the increased dependency of ras for F2,6BP-activated glycolysis supports the previously reported shift by oncogenic ras away from oxidative phosphorylation and toward aerobic glycolytic flux to lactate (Mazurek et al, 2001;Ramanathan et al, 2005;Vizan et al, 2005). We postulate that the combination of reduced intracellular F2,6BP and an increased need for high PFK-1 flux may sensitize ras-transformed cells to the effects of PFKFB3 inhibition.…”

Section: Discussionsupporting

confidence: 86%

“…The oncogene ras has recently emerged as a central regulator of enhanced glucose uptake and glycolysis in neoplastic cells (Mazurek et al, 2001;Blum et al, 2005;Ramanathan et al, 2005;Vizan et al, 2005). Stable transfection of oncogenic H-ras V12 into Rat-1 immortalized fibroblasts causes increased glucose uptake and lactate production (Racker et al, 1985;Kole et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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Ras transformation requires metabolic control by 6-phosphofructo-2-kinase

et al. 2006

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Neoplastic cells transport large amounts of glucose in order to produce anabolic precursors and energy within the inhospitable environment of a tumor. The ras signaling pathway is activated in several cancers and has been found to stimulate glycolytic flux to lactate. Glycolysis is regulated by ras via the activity of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFK2/FBPase), which modulate the intracellular concentration of the allosteric glycolytic activator, fructose-2,6-bisphosphate (F2,6BP). We report herein that sequential immortalization and ras-transformation of mouse fibroblasts or human bronchial epithelial cells paradoxically decreases the intracellular concentration of F2,6BP. This marked reduction in the intracellular concentration of F2,6BP sensitizes transformed cells to the antimetabolic effects of PFK2/FBPase inhibition. Moreover, despite co-expression of all four mRNA species (PFKFB1-4), heterozygotic genomic deletion of the inducible PFKFB3 gene in rastransformed mouse lung fibroblasts suppresses F2,6BP production, glycolytic flux to lactate, and growth as soft agar colonies or tumors in athymic mice. These data indicate that the PFKFB3 protein product may serve as an essential downstream metabolic mediator of oncogenic ras, and we propose that pharmacologic inhibition of this enzyme should selectively suppress the high rate of glycolysis and growth by cancer cells.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Ras transformation requires metabolic control by 6-phosphofructo-2-kinase

et al. 2006

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“…Tumors with oncogenic RAS correlate with numerous metabolic aberrations, including increased consumption of glucose and glutamine, increased production of lactic acid, altered expression of mitochondrial genes, and reduced mitochondrial activity (35)(36)(37)(38). Our findings, that a glycolysis gene signature is specifically upregulated in KRAS-mutant lung tumors and that KRAS-mutant cells are more sensitive to the glycolysis inhibitor 2-DG, are consistent with such changes in tumor metabolism.…”

Section: Discussionsupporting

confidence: 80%

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

106

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Purpose: This study is aimed to identify genes within the KRAS genomic amplicon that are both coupregulated and essential for cell proliferation when KRAS is amplified in lung cancer.Experimental Design: We used an integrated genomic approach to identify genes that are coamplified with KRAS in lung adenocarcinomas and subsequently preformed an RNA interference (RNAi) screen to uncover functionally relevant genes. The role of lactate dehydrogenase B (LDHB) was subsequently investigated both in vitro and in vivo by siRNA and short hairpin RNA (shRNA)-mediated knockdown in a panel of lung adenocarcinoma cells lines. LDHB expression was also investigated in patient tumors using microarray and immunohistochemistry analyses.Results: RNAi-mediated depletion of LDHB abrogated cell proliferation both in vitro and in xenografted tumors in vivo. We find that LDHB expression correlates to both KRAS genomic copy number gain and KRAS mutation in lung cancer cell lines and adenocarcinomas. This correlation between LDHB expression and KRAS status is specific for lung cancers and not other tumor types that harbor KRAS mutations. Consistent with a role for LDHB in glycolysis and tumor metabolism, KRAS-mutant lung tumors exhibit elevated expression of a glycolysis gene signature and are more dependent on glycolysis for proliferation compared with KRAS wild-type lung tumors. Finally, high LDHB expression was a significant predictor of shorter survival in patients with lung adenocarcinomas.Conclusion: This study identifies LDHB as a regulator of cell proliferation in a subset of lung adenocarcinoma and may provide a novel therapeutic approach for treating lung cancer.

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“…Early evidence has showed that cells harboring constitutive K-ras expression increased glucose uptake and lactate production [53][54][55][56]. Subsequent reports have also demonstrated that human colon cancer cell lines and K-ras transformed NIH3T3 fibroblast could also rely upon glutamine metabolism through functional mitochondrial activity [10,57].…”

Section: K-rasmentioning

confidence: 99%

Glutamine at focus: versatile roles in cancer

2015

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Your article is protected by copyright and all rights are held exclusively by International Society of Oncology and BioMarkers (ISOBM).Abstract During the past decade, a heightened understanding of metabolic pathways in cancer has significantly increased. It is recognized that many tumor cells are genetically programmed and have involved an abnormal metabolic state. Interestingly, this increased metabolic autonomy generates dependence on various nutrients such as glucose and glutamine. Both of these components participate in various facets of metabolic activity that allow for energy production, synthesis of biomass, antioxidant defense, and the regulation of cell signaling. Here, we outline the emerging data on glutamine metabolism and address the molecular mechanisms underlying glutamine-induced cell survival. We also discuss novel therapeutic strategies to exploit glutamine addiction of certain cancer cell lines.

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K-ras Codon-Specific Mutations Produce Distinctive Metabolic Phenotypes in Human Fibroblasts

Cited by 106 publications

References 17 publications

Ras transformation requires metabolic control by 6-phosphofructo-2-kinase

Ras transformation requires metabolic control by 6-phosphofructo-2-kinase

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

Glutamine at focus: versatile roles in cancer

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