The multifaceted activities of AMPK in tumor progression-why the “one size fits all” definition does not fit at all?

Gantner, Benjamin N.

doi:10.1002/iub.1213

Cited by 43 publications

(34 citation statements)

References 83 publications

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“…Cellular ATP becomes depleted, leading to energy collapse and cell death. This is consistent with previous reports of the ability of AMPK signalling to maintain ATP levels in response to hypoxia, fuel deprivation, and other stressors [35]. Interestingly, non-cancer cells do not appear to be sensitized to the cytotoxic effects of metformin by glucose deprivation (see Fig.…”

Section: Discussionsupporting

confidence: 92%

Mechanisms by Which Low Glucose Enhances the Cytotoxicity of Metformin to Cancer Cells Both In Vitro and In Vivo

et al. 2014

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Different cancer cells exhibit altered sensitivity to metformin treatment. Recent studies suggest these findings may be due in part to the common cell culture practice of utilizing high glucose, and when glucose is lowered, metformin becomes increasingly cytotoxic to cancer cells. In low glucose conditions ranging from 0 to 5 mM, metformin was cytotoxic to breast cancer cell lines MCF7, MDAMB231 and SKBR3, and ovarian cancer cell lines OVCAR3, and PA-1. MDAMB231 and SKBR3 were previously shown to be resistant to metformin in normal high glucose medium. When glucose was increased to 10 mM or above, all of these cell lines become less responsive to metformin treatment. Metformin treatment significantly reduced ATP levels in cells incubated in media with low glucose (2.5 mM), high fructose (25 mM) or galactose (25 mM). Reductions in ATP levels were not observed with high glucose (25 mM). This was compensated by enhanced glycolysis through activation of AMPK when oxidative phosphorylation was inhibited by metformin. However, enhanced glycolysis was either diminished or abolished by replacing 25 mM glucose with 2.5 mM glucose, 25 mM fructose or 25 mM galactose. These findings suggest that lowering glucose potentiates metformin induced cell death by reducing metformin stimulated glycolysis. Additionally, under low glucose conditions metformin significantly decreased phosphorylation of AKT and various targets of mTOR, while phospho-AMPK was not significantly altered. Thus inhibition of mTOR signaling appears to be independent of AMPK activation. Further in vivo studies using the 4T1 breast cancer mouse model confirmed that metformin inhibition of tumor growth was enhanced when serum glucose levels were reduced via low carbohydrate ketogenic diets. The data support a model in which metformin treatment of cancer cells in low glucose medium leads to cell death by decreasing ATP production and inhibition of survival signaling pathways. The enhanced cytotoxicity of metformin against cancer cells was observed both in vitro and in vivo.

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Section: Discussionsupporting

confidence: 92%

Mechanisms by Which Low Glucose Enhances the Cytotoxicity of Metformin to Cancer Cells Both In Vitro and In Vivo

et al. 2014

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“…Gene silencing studies demonstrating that inhibition of AMPK did not prevent cell death advocate an alternate role of AMPK in fisetin treated melanoma cells (Fig.6). The notion that AMPK acts solely as a tumor suppressor conflicts with reports that show that it confers resistance to nutrient deprivation, sustains NADPH levels in cancer cells, facilitates stress-induced gene transcription, promotes cell survival and increases malignant transformation (45, 46). It seems plausible that fisetin mediated activation of AMPK may be part of a multi-pronged defense mechanism mounted by the cellular machinery subsequent to alterations in cellular energy levels.…”

Section: Discussionmentioning

confidence: 90%

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

Syed

Lall

Chamcheu

et al. 2014

Archives of Biochemistry and Biophysics

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The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up- regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16 days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMPK-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity.

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“…AMPK is known to be important in energy homeostasis, and is considered a major switch, regulating glucose and lipid metabolism (38). In abnormal conditions, including starvation, hypoxia and oxidative stress, activated AMPK promotes cell survival (39). In the liver, AMPK switches on ATP-producing processes and inhibits ATP-consuming anabolic processes (40), and it has been reported that treatment with the AMPK agonist, 5-aminoimidazole carboxamide ribonucleotide, can induce the expression levels of metabolic genes and enhance running endurance (41).…”

Section: Discussionmentioning

confidence: 99%

Investigations on the antifatigue and antihypoxic effects of Paecilomyces hepiali extract

Wang

Liu

et al. 2015

Molecular Medicine Reports

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Abstract. Paecilomyces hepiali, one of the most valuable and effective Chinese medicinal herbs, possesses potential antioxidant, immunomodulatory, antitumor and anti-inflammatory properties. The present study aimed to investigate the antifatigue and antihypoxic effects of Paecilomyces hepiali extract (PHC) in a mouse model. Using a rotating rod, forced swimming and running assessment, the antifatigue activity of PHC was determined. PHC administration for 7 days had no effect on mouse horizontal or vertical movement, indicating no neurotoxicity at the selected doses was observed. Using a normobaric hypoxia, sodium nitrite toxicosis and acute cerebral ischemia assessments, PHC was confirmed to possess antihypoxic effects. PHC treatment for 7 days significantly enhanced the serum and liver levels of adenosine triphosphate, superoxide dismutase and glutathione peroxidase, prior to and following 60 min of swimming. The levels of antioxidant-associated proteins in the livers of the mice were analyzed using western blotting. PHC effectively increased the expression levels of phosphorylated (p)-5'-monophosphate (AMP)-activated protein kinase (AMPK), p-protein kinase B (AKT) and p-mammalian target of rapamycin (mTOR). The results of the present study demonstrated that PHC efficiently enhanced endurance from fatigue and had antihypoxic effects through elevation of the antioxidant capacity in the serum and liver, at least in part through the AMPK and AKT/mTOR pathways. These results indicate the potential of this natural product as an antioxidant in the treatment of fatigue, hypoxia and their associated diseases.

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The multifaceted activities of AMPK in tumor progression-why the “one size fits all” definition does not fit at all?

Cited by 43 publications

References 83 publications

Mechanisms by Which Low Glucose Enhances the Cytotoxicity of Metformin to Cancer Cells Both In Vitro and In Vivo

Mechanisms by Which Low Glucose Enhances the Cytotoxicity of Metformin to Cancer Cells Both In Vitro and In Vivo

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

Investigations on the antifatigue and antihypoxic effects of Paecilomyces hepiali extract

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