Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was undertaken to interrogate cancer cell survival during long-term hypoxic stress. Two systems with relevance to carcinogenesis were employed: Fully transformed BJ cells and a renal carcinoma cell line (786-0). The dynamic of AMPK activity was consistent with a prosurvival role during chronic hypoxia. This was further supported by the effects of AMPK agonists and antagonists (AICAR and compound C). Expression of a dominant-negative AMPK alpha resulted in a decreased ATP level and significantly compromised survival in hypoxia. Dose-dependent prosurvival effects of rapamycin were consistent with mTOR inhibition being a critical downstream mediator of AMPK in persistent low oxygen.
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PMID:AMP-activated protein kinase is essential for survival in chronic hypoxia. 1835 90

Mutation of LKB1 is the key molecular event underlying Peutz-Jeghers syndrome, a dominantly inherited condition characterized by a predisposition to a range of malignancies, including those of the reproductive system. We report here the use of a Cre-LoxP strategy to directly address the role of Lkb1 in prostate neoplasia. Recombination of a LoxP-flanked Lkb1 allele within all four murine prostate lobes was mediated by spontaneous activation of a p450 CYP1A1-driven Cre recombinase transgene (termed AhCre). Homozygous mutation of Lkb1 in males expressing AhCre reduced longevity, with 100% manifesting atypical hyperplasia and 83% developing prostate intraepithelial neoplasia (PIN) of the anterior prostate within 2 to 4 months. We also observed focal hyperplasia of the dorsolateral and ventral lobes (61% and 56% incidence, respectively), bulbourethral gland cysts associated with atypical hyperplasia (100% incidence), hyperplasia of the urethra (39% incidence), and seminal vesicle squamous metaplasia (11% incidence). PIN foci overexpressed nuclear beta-catenin, p-Gsk3 beta, and downstream Wnt targets. Immunohistochemical analysis of foci also showed a reduction in Pten activation and up-regulation of both p-PDK1 (an AMPK kinase) and phosphorylated Akt. Our data are therefore consistent with deregulation of Wnt and phosphoinositide 3-kinase/Akt signaling cascades after loss of Lkb1 function. For the first time, this model establishes a link between the tumor suppressor Lkb1 and prostate neoplasia, highlighting a tumor suppressive role within the mouse and raising the possibility of a similar association in the human.
Cancer Res 2008 Apr 01
PMID:Lkb1 deficiency causes prostate neoplasia in the mouse. 1838 28

The LKB1 tumour suppressor phosphorylates and activates AMPK (AMP-activated protein kinase) when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 (mammalian target of rapamycin complex 1) kinase that is activated in the majority of human cancers. Blood glucose-lowering Type 2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In the present study, we investigated the importance of the LKB1-AMPK pathway in regulating tumorigenesis in mice resulting from deficiency of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor, which drives cell growth through overactivation of the Akt and mTOR (mammalian target of rapamycin) kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumorigenesis on its own, but markedly accelerates tumour development in PTEN(+/-) mice. In contrast, activating the AMPK pathway by administration of metformin, phenformin or A-769662 to PTEN(+/-) mice significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN-deficient cells. Our findings highlight, using an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumorigenesis resulting from loss of the PTEN tumour suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1 pathway is activated. Most importantly, our results demonstrate the potential of AMPK activators, such as clinically approved metformin, as anticancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.
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PMID:Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. 1846 13

The compound 2-deoxyglucose (2-DG) enhances chemotherapy/radiotherapy in cell lines and animal models, prompting two phase I clinical trials with this cancer therapeutic. Although its mechanism of action has not been fully elucidated, it is hypothesized that the molecular basis of 2-DG activity is related to glycolysis inhibition. Here, we report that 2-DG induced Akt phosphorylation at Thr(308) and Ser(473) as early as 15 min post-treatment. These phosphorylation events required phosphatidylinositol-3-kinase activity but were not related to LKB1/AMP-activated protein kinase signaling, the inhibition of glycolysis or epidermal growth factor receptor signaling. The 2-DG-mediated Akt phosphorylation also led to the phosphorylation of Akt downstream targets, such as Foxo3a, GSK3beta, and Chk1. Because the functional consequence of Akt activation includes chemotherapy/radiotherapy resistance, our data suggested that the combination of phosphatidylinositol-3-kinase/Akt inhibitory agents in 2-DG-based chemotherapy/radiotherapy may result in enhanced therapeutic efficacy.
Mol Cancer Ther 2008 Apr
PMID:2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition. 1841 94

Does the LKB1-AMPK (AMP-activated protein kinase) pathway act to suppress tumorigenesis or to rescue cancer cells from metabolic collapse? New work from the Alessi laboratory in this issue of the Biochemical Journal shows conclusively that AMPK activators delay the growth of tumours that occur spontaneously in PTEN (phosphatase and tensin homologue deleted on chromosome 10) heterozygous mice.
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PMID:Cancer therapy: staying current with AMPK. 1838

The observation that genistein may behave as a pro-oxidant agent lead us to examine the capacity of this isoflavone to modulate the toxicity of the oxidation-sensitive anti-leukemic agent arsenic trioxide (ATO), and for comparison other anti-tumor drugs. Co-treatment with genistein increased ATO-provoked apoptosis and activated apoptosis regulatory events (Bcl-X(L) down-regulation, cytochrome c and Omi/HtrA2 release from mitochondria, XIAP decrease and caspase-8/Bid and caspase-3 activation) in U937 promonocytes and other human leukemia cell lines (HL60, THP-1, Jurkat, RPMI-8866), but not in phytohemagglutinin-stimulated non-tumor peripheral blood lymphocytes (PBLs). Genistein, alone and with ATO, stimulated reactive oxygen species generation, and apoptosis was attenuated by N-acetyl-L-cysteine and butylated hydroxyanisole. Addition of low H(2)O(2) concentrations mimicked the capacity of genistein to increase ATO-provoked apoptosis in leukemia cells, but not in PBLs. By contrast, co-treatment with genistein or H(2)O(2) failed to potentiate the toxicity of DNA-targeting agent cisplatin, the proteasome inhibitor MG-132 and the histone deacetylase inhibitor MS-275. Within the here used time-period (14 hr) genistein, alone or with ATO, did not significantly affect Akt phosphorylation and NF-kappaB binding activity, nor decreased intracellular GSH content. However, it elicited N-acetyl-L-cysteine-inhibitable phosphorylation of p38-MAPK and AMPK, and apoptosis was attenuated by pharmacologic inhibitors against these kinases. The pro-oxidant capacity of genistein might be exploited to improve the efficacy of ATO as anti-leukemic agent, and perhaps the efficacy of other oxidation-based therapeutic approaches.
Int J Cancer 2008 Sep 01
PMID:Genistein selectively potentiates arsenic trioxide-induced apoptosis in human leukemia cells via reactive oxygen species generation and activation of reactive oxygen species-inducible protein kinases (p38-MAPK, AMPK). 1854 68

Macroautophagy (called autophagy hereafter) is a catabolic process activated by various types of stress, most notably by nutrient deprivation. The autophagic degradation of intracellular macromolecules provides metabolic support for the cell; however, this physiological process can also initiate a form of cell death (type 2 programmed cell death). Here we report that oxygen deprivation can activate the autophagic pathway in human cancer cell lines. We observed that hypoxia induced distinct cellular changes characteristic of autophagy such as an increase in cytoplasmic acidic vesicles, and processing and cellular localization of microtubule-associated protein-1 light chain 3. Oxygen deprivation-induced autophagy did not require nutrient deprivation, hypoxia-inducible factor-1 (HIF-1) activity, or expression of the HIF-1 target gene BNIP3 (Bcl-2 adenovirus E1a nineteen kilodalton interacting protein 3) or BNIP3L (BNIP3 like protein). Hypoxia-induced autophagy involved the activity of 5'-AMP-activated protein kinase (AMPK). Finally, we determined that cells lacking the autophagy gene ATG5 were unable to activate the autophagic machinery in hypoxia, had decreased oxygen consumption and increased glucose uptake under hypoxia, had increased survival in hypoxic environments, and exhibited accelerated growth as xenografted tumors. Together, these findings suggest that the autophagic degradation of cellular macromolecules contributes to the energetic balance governed by AMPK, and that suppression of autophagy in transformed cells can increase both resistance to hypoxic stress and tumorigenicity.
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PMID:Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. 1855 Nov 30

Dietary energy restriction (DER) inhibits mammary carcinogenesis, yet mechanisms accounting for its protective activity have not been fully elucidated. In this study, we tested the hypothesis that DER exerts effects on intracellular energy sensing pathways, resulting in alterations of phosphorylated proteins that play a key role in the regulation of cancer. Experiments were conducted using the 1-methyl-1-nitrosourea-induced mammary cancer model in which rats were 0%, 20%, or 40% energy restricted during the postinitiation stage of carcinogenesis. Parallel experiments were done in non-carcinogen-treated rats in which effects of DER at 0%, 5%, 10%, 20%, or 40% in liver were investigated. In a DER dose-dependent manner, levels of Thr(172) phosphorylated AMP-activated protein kinase (AMPK) increased in mammary carcinomas with a concomitant increase in phosphorylated acetyl-CoA-carboxylase, a direct target of AMPK, the phosphorylation of which is regarded as an indicator of AMPK activity. Levels of phosphorylated mammalian target of rapamycin (mTOR) decreased with increasing DER, and down-regulation of mTOR activity was verified by a decrease in the phosphorylation state of two mTOR targets, 70-kDa ribosomal protein S6 kinase (p70S6K) and eukaryote initiation factor 4E binding protein 1 (4E-BP1). Coincident with changes in mTOR phosphorylation, levels of activated protein kinase B (Akt) were also reduced. Similar patterns were observed in mammary glands and livers of non-carcinogen-treated rats. This work identifies components of intracellular energy sensing pathways, specifically mTOR, its principal upstream regulators, AMPK and Akt, and its downstream targets, p70S6K and 4E-BP1, as candidate molecules on which to center mechanistic studies of DER.
Cancer Res 2008 Jul 01
PMID:Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver. 1859 53

ErbB2 targeted therapies represent an attractive strategy in breast cancer. Herceptin, an anti-ErbB2 monoclonal antibody, is an approved treatment for patients with ErbB2-overexpressing breast cancers. ErbB2 signaling can also be blocked using small molecule tyrosine kinase inhibitors, like Lapatinib, that compete with ATP for binding at the ErbB2 catalytic kinase domain. The principal adverse event attributable to Herceptin is cardiac toxicity. Data from clinical trials show that, unlike Herceptin, Lapatinib may have reduced cardiac toxicity. This study was conducted to elucidate pathways which may contribute to cardiac toxicity or survival using Lapatinib and Herceptin. Our results show that treatments directed to ErbB1/2 receptors using GW-2974 (a generic ErbB1/2 inhibitor) activated AMPK, a key regulator in mitochondrial energy production pathways in human cardiac cells and cancer cells. Although Herceptin downregulates tumor survival pathways, AMPK fails to be activated in tumor and cardiac cells. When treated in combination with TNFalpha, a known cytokine associated with cardiac toxicity, GW-2974 protected cardiac cells from cell death whereas Herceptin contributed to TNFalpha-induced cellular killing. Since activity of AMPK in cardiac cells is associated with stress induced survival in response to cytokines or energy depletion, cardiac toxicity by Herceptin may be a consequence of failure to induce stress-related survival mechanisms. Thus, the ability to activate AMPK after treatment with tyrosine kinase inhibitors may be a crucial factor for increased efficacy against the tumor and decreased risk of cardiomyopathy.
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PMID:Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. 1859 1

AMP-activated protein kinase (AMPK) is a widely conserved Ser/Thr-specific protein kinase, homologous to Saccharomyces cerevisiae Snf1, and involved in nutrient sensing in lower organisms. In 2003, we reviewed the role of this enzyme in glucose homeostasis in mammals [Rutter, G.A., daSilvaXavier, G., Leclerc, I., 2003. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem. J. 375 (Pt 1), 1-16]. In the subsequent 5 years, dramatic strides have taken place in our understanding of the role of AMPK in the control of whole body metabolic homeostasis, the regulation of the enzyme by upstream kinases, and its molecular structure. These new studies and earlier work arguably propel AMPK, and perhaps related family members into a "super league" of potential therapeutic targets for maladies including diabetes, cancer, heart disease, and obesity. Here, we survey some of these recent advances, focussing on the role of this and related enzymes in the control of pancreatic beta-cell function and glucose homeostasis.
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PMID:The AMP-regulated kinase family: enigmatic targets for diabetes therapy. 1861 32


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