Targeting AMPK for cancer prevention and treatment

Li, Weidong; Saud, Shakir M.; Young, Matthew R.; Chen, Guohong; Bai, Hua

doi:10.18632/oncotarget.3629

Cited by 313 publications

(253 citation statements)

References 148 publications

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“…At the same time, activated AMPK stimulates catabolism of fatty acids and glucose uptake. Additionally, AMPK inhibits cell proliferation by stabilizing the tumor suppressors tuberous sclerosis 2 protein and p53 and by regulating the cyclin-dependent kinase inhibitors p21 and p27; this implicates AMPK as a potential target for cancer treatment (51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Galdieri¹,

Gatla

Vancurova

et al. 2016

Journal of Biological Chemistry

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Edited by Alex TokerAMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetylCoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects.Acetylation is one of the epigenetic post-translational modifications of histones; it affects chromatin structure and regulates diverse cellular functions, such as gene expression, DNA replication and repair, and cellular proliferation (1, 2). Acetylation and deacetylation of chromatin histones, mediated by histone acetyltransferases (HATs) 3 and histone deacetylases (HDACs), respectively, represent the major mechanisms for epigenetic gene regulation. The dynamic balance between histone acetylation and deacetylation, mediated by the activities of HATs and HDACs, is stringently regulated in healthy cells but is often dysregulated in cancer (3, 4).Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment (5). In mammalian cells, the nucleocytosolic enzyme ATP-citrate lyase is the major source of acetyl-CoA for histone acetylation (6). Another mechanism for generation of acetyl-CoA in the nucleus involves translocation of pyruvate dehydrogenase from mitochondria to the nucleus (7). In yeast, global histone acetylation depends on nucleocytosolic acetyl-CoA produced by acetyl-CoA synthetase (5). In both yeast and mammalian cells, the nucleocytosolic acetyl-CoA is the link among cellular energy, carbon metabolism, histone acetylation, ...

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Section: Discussionmentioning

confidence: 99%

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Galdieri¹,

Gatla

Vancurova

et al. 2016

Journal of Biological Chemistry

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“…Recent studies have revealed that activation of AMPK by pharmaceuticals or natural compounds, e.g. bitter melon extract (BME), is able to block the malignant cell growth in numerous human cancers [42][43][44][45][46]. Indeed, previous studies reported by our team showed that pharmaceutical AMPK activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) (ATP-dependent) and A23187 (ATP-independent) could be used to suppress cervical cancer cell growth harboring with or without LKB1, an upstream kinase of AMPK [44].…”

Section: Amp-activated Protein Kinase In Human Cancer and Its Signifimentioning

confidence: 99%

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

Yung

Ngan

Chan

2016

ABBS

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The development and strategic application of effective anticancer therapies have turned out to be one of the most critical approaches of managing human cancers. Nevertheless, drug resistance is the major obstacle for clinical management of these diseases especially ovarian cancer. In the past years, substantial studies have been carried out with the aim of exploring alternative therapeutic approaches to enhance efficacy of current chemotherapeutic regimes and reduce the side effects caused in order to produce significant advantages in overall survival and to improve patients' quality of life. Targeting cancer cell metabolism by the application of AMP-activated protein kinase (AMPK)-activating agents is believed to be one of the most plausible attempts. AMPK activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside, A23187, metformin, and bitter melon extract not only prevent cancer progression and metastasis but can also be applied as a supplement to enhance the efficacy of cisplatin-based chemotherapy in human cancers such as ovarian cancer. However, because of the undesirable outcomes along with the frequent toxic side effects of most pharmaceutical AMPK activators that have been utilized in clinical trials, attentions of current studies have been aimed at the identification of replaceable reagents from nutraceuticals or traditional medicines. However, the underlying molecular mechanisms of many nutraceuticals in anticancer still remain obscure. Therefore, better understanding of the functional characterization and regulatory mechanism of natural AMPK activators would help pharmaceutical development in opening an area to intervene ovarian cancer and other human cancers.

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“…Recently, activation of the AMPK signaling pathway has been shown to play a critical role in regulation of energy metabolism under both physiological and pathological conditions via downstream pathways relevant to the control of cellular proliferation (16,17). AMPK is known to function as an intracellular energy sensor, being activated in response to an increased AMP⁄ATP ratio, a condition of energetic stress, to promote the catabolic pathway, thereby inhibiting cell proliferation (18,19).…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence now indicates that cancer metabolism mediates cancer development and progression via its activation of related signaling pathways, such as the AMP-activated protein kinase (AMPK) pathway (16,17). Under metabolic stress conditions, where decreases in intracellular ATP and increases in AMP levels are common, AMPK is activated by phosphorylation of a critical amino acid residue (Thr172) to function as a major metabolic switch that maintains energy homeostasis (18,19).…”

Section: Introductionmentioning

confidence: 99%

Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

Park

Jeong

Jeong³

et al. 2015

International Journal of Oncology

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Abstract. The Kalopanax septemlobus leaf (Thunb.) Koidz. has been used as a traditional medicine herb for the treatment of various human diseases for hundreds of years. In this study, we investigated the mechanism underlying the inhibitory effects of an ethanol extract of K. septemlobus leaf (EEKS) on proliferation of HepG2 hepatocellular carcinoma cells. For this study, cell viability and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, DAPI (4,6-diamidino-2-phenylindole) staining, agarose gel electrophoresis, and flow cytometry. Measurements of the mitochondrial membrane potential (MMP), caspase activity assays and western blots were conducted to determine whether HepG2 cell death occurred by apoptosis. Treatment of HepG2 cells with EEKS concentration-dependently reduced cell survival while significantly increasing the ratio of apoptotic cells. EEKS treatment increased the levels of the death receptors (DRs), DR4 and DR5, and activated caspases, as well as promoting proteolytic degradation of poly(ADP-ribose)-polymerase associated with the downregulation of protein expression of members of the inhibitor of apoptosis protein family. Treatment with EEKS also caused truncation of Bid, translocation of pro-apoptotic Bax to the mitochondria, and loss of mitochondrial membrane permeabilization, thereby inducing the release of cytochrome c into the cytosol. However, treatment of HepG2 cells with a pan-caspase inhibitor reversed EEKS-induced apoptosis and growth suppression, indicating that EEKS appears to induce apoptosis though a caspase-dependent mechanism involving both intrinsic and extrinsic apoptotic pathways. In addition, the phosphorylation level of AMP-activated protein kinase (AMPK) was elevated when cells were exposed to EEKS. A specific inhibitor for AMPK attenuated the EEKS-induced activation of caspases, and consequently prevented the EEKS-induced apoptosis and reduction in cell viability. Overall, our findings suggest that EEKS inhibits the growth of HepG2 cells by inducing AMPK-mediated caspase-dependent apoptosis, suggesting the potential therapeutic application of EEKS in the treatment or prevention of cancers.

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Targeting AMPK for cancer prevention and treatment

Cited by 313 publications

References 148 publications

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

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