Akt Stimulates Aerobic Glycolysis in Cancer Cells

Elstrom, Rebecca; Bauer, Daniel E.; Buzzai, Monica; Karnauskas, Robyn; Harris, Marian H.; Plas, David R.; Zhuang, Hongming; Cinalli, Ryan M.; Alavi, Abass; Rudin, Charles M.; Thompson, Craig B.

doi:10.1158/0008-5472.can-03-2904

Cited by 1,310 publications

(1,136 citation statements)

References 34 publications

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“…This makes cells hypersensitive to glucose deprivation, as the cell is stimulated to proliferate but it lacks the building blocks needed for this purpose. For instance, hyperactivation of the oncogenic Akt/mTOR pathway promotes sensitivity to glucose withdrawal (Elstrom et al, 2004). Downstream of Akt, hyperactivation of mTOR, for instance, owing to the lack of tumor suppressor TSC1/2, promotes sensitivity to starvation.…”

Section: Oncogenes Promote Sensitivity To Glucose Deprivationmentioning

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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Section: Oncogenes Promote Sensitivity To Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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“…Human cancers express two common metabolic phenotypes, aerobic glycolysis 12 and lipogenesis. 36 The combination of aerobic glycolysis and increased de novo fatty acid synthesis is not a frequent finding in normal human tissues, and is largely unique to cancer cells.…”

Section: Ampk Activation In Cancer Cellsmentioning

confidence: 99%

“…11 Despite access to adequate oxygen, cancer cells continue to rely on glycolysis over respiration to generate ATP. 12 Exclusive reliance on glycolysis could provide advantages to the cancer cell under hypoxic conditions, but it also belies an inflexibility regarding energy management. The inability to switch between glycolysis and respiration depending on the extracellular environment could yield strategies for cancer therapy.…”

Section: Introduction and Historical Perspectivementioning

confidence: 99%

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Kuhajda

2008

Int J Obes

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AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

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“…Accordingly, even in the presence of oxygen, cancer cells tend to synthesize ATP mainly through anaerobic glycolysis, a phenomenon that requires high glucose uptake and causes local acidification owing to lactate production (Warburg, 1930(Warburg, , 1956). The Warburg effect may involve a series of metabolic defects including unregulated, supernormal glucose uptake with upregulation of the rate-limiting steps of glycolysis (for instance driven by constitutive activation of the Akt pathway) (Elstrom et al, 2004), as well as defects in mitochondrial respiration, as they manifest in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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Akt Stimulates Aerobic Glycolysis in Cancer Cells

Cited by 1,310 publications

References 34 publications

Sugar-free approaches to cancer cell killing

Sugar-free approaches to cancer cell killing

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Mitochondria as therapeutic targets for cancer chemotherapy

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