Targeting metabolic transformation for cancer therapy

Tennant, Daniel A.; Durán, Raúl V.; Gottlieb, Eyal

doi:10.1038/nrc2817

Cited by 967 publications

(826 citation statements)

References 127 publications

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“…The new interest in cancer metabolism already has an impact in the clinic, both in diagnosis (Pauwels et al, 2000) and therapy (Tennant et al, 2010). In the next sections, we review cancer metabolic reprogramming, emphasizing its dynamic intertwining with key events occurring during malignant transformation.…”

Section: The Warburg Effectmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed.

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Section: The Warburg Effectmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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“…Indeed, drugs that interfere with nucleic acid metabolism, such as methotrexate or 5-FU, have been used for decades to treat tumors. We could thus interfere with tumor metabolism at multiple levels: either depleting tumor cells of their preferred nutrients or inhibiting intracellular catabolic or biosynthetic pathways altered in tumors (Pelicano et al, 2006;Kroemer and Pouyssegur, 2008;Pathania et al, 2009;Tennant et al, 2010). In the present review, we will focus on glucose metabolism as a target for tumor therapy.…”

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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“…Cancer metabolism is a highly dynamic network that adapts to changes in environmental conditions. However, metabolic reprogramming produces selective dependencies in cancer cells [4] and metabolic enzymes may provide suitable targets for the development of novel treatment strategies [5,6].…”

Section: Introductionmentioning

confidence: 99%

Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival

Baenke

Dubuis

Brault³

et al. 2015

The Journal of Pathology

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Metabolic reprogramming in cancer enhances macromolecule biosynthesis and supports cell survival. Oncogenic drivers affect metabolism by altering distinct metabolic processes and render cancer cells sensitive to perturbations of the metabolic network. This study aimed to identify selective metabolic dependencies in breast cancer by investigating 17 breast cancer cells lines representative of the genetic diversity of the disease. Using a functional screen, we demonstrate here that monocarboxylate transporter 4 (MCT4) is an important regulator of breast cancer cell survival. MCT4 supports pH maintenance, lactate secretion and non-oxidative glucose metabolism in breast cancer cells. Moreover, MCT4 depletion caused an increased dependence of cancer cells on mitochondrial respiration and glutamine metabolism. MCT4 depletion reduced the ability of breast cancer cells to grow in a three-dimensional (3D) matrix or as multilayered spheroids. Moreover, MCT4 expression is regulated by the PI3K-Akt signalling pathway and highly expressed in HER2-positive breast cancers. These results suggest that MCT4 is a potential therapeutic target in defined breast cancer subtypes and reveal novel avenues for combination treatment.

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Targeting metabolic transformation for cancer therapy

Cited by 967 publications

References 127 publications

Metabolic reprogramming of the tumor

Metabolic reprogramming of the tumor

Sugar-free approaches to cancer cell killing

Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival

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