Ras-dependent carbon metabolism and transformation in mouse fibroblasts

Chiaradonna, Ferdinando; Sacco, Elena; Manzoni, Romilde; Giorgio, Marco; Vanoni, Marco; Alberghina, Lilia

doi:10.1038/sj.onc.1209528

Cited by 101 publications

(94 citation statements)

References 77 publications

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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: 74%

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

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

110

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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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Section: Discussionsupporting

confidence: 74%

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

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

110

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“…Akt stimulates membrane localization of glucose transporters and enhances transcription or activity of glycolytic enzymes such as hexokinase and phosphofructokinase (Gottlob et al, 2001;Rathmell et al, 2003). K-Ras promotes transcription of several glycolytic enzymes (Chiaradonna et al, 2006). Conversely, tumor suppressors such as PTEN (inhibitor of the PI3K/Akt pathway) or p53 downregulate glycolysis.…”

Section: Metabolic Transformation: Cancer's Friend and Foementioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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“…18 So, whereas normal NIH3T3 cells cope with glucose shortage by relying on oxidative metabolism and decelerating cell proliferation, K-ras-transformed cells are remarkably sensitive to glucose deprivation, losing their growth advantage and high survival rate. 19 Analysis of GSK-3␤ regulation in K-ras-transformed fibroblasts and their parental counterparts in conditions of high versus low glucose availability showed posttranslational inhibition of GSK-3␤ in the latter condition. This pattern was uncoupled from regulation of glycogen synthase and ␤-catenin.…”

mentioning

confidence: 99%

Nutritional Limitation Sensitizes Mammalian Cells to GSK-3β Inhibitors and Leads to Growth Impairment

Candia

Minopoli

Verga

et al. 2011

The American Journal of Pathology

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The serine/threonine kinase GSK-3␤ was initially described as a key enzyme involved in glucose metabolism, but it is now known to regulate a wide range of biological processes, including proliferation and apoptosis. We previously reported a transformation-dependent cell death induced by glucose limitation in K-ras-transformed NIH3T3. To address the mechanism of this phenomenon, we analyzed GSK-3␤ regulation in these cells in conditions of high versus low glucose availability. We found that glucose depletion caused a marked inhibition of GSK-3␤ through posttranslational mechanisms and that this inhibition was much less pronounced in normal cells. Further inhibition of GSK-3␤ with lithium chloride, combined with glucose shortage, caused specific activation of AMPactivated protein kinase and significant suppression of proliferation in transformed but not normal cells. The cooperative effect of lithium and low glucose availability on cell growth did not seem to depend exclusively on ras pathway activation because two human cell lines, A549 and MDA-MB-231, both harboring an activated ras gene, showed very different sensitivity to lithium. These findings thus provide a rationale to further analyze the biochemical bases for combined glucose deprivation and GSK-3␤ inhibition as a new approach to control transformed cell growth.

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Ras-dependent carbon metabolism and transformation in mouse fibroblasts

Cited by 101 publications

References 77 publications

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

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

Sugar-free approaches to cancer cell killing

Nutritional Limitation Sensitizes Mammalian Cells to GSK-3β Inhibitors and Leads to Growth Impairment

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