Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMPK is a serine/threonine protein kinase family and we recently identified a novel member, ARK5. The activation of ARK5 is triggered by Akt, and ARK5 induces tumor cell survival during nutrient starvation. In the current study, we investigated the mechanisms of induction of cell survival by ARK5. Human hepatoma HepG2 cells undergo necrotic cell death within 24 h after the start of glucose starvation, and the cell death signaling has been found to be mediated by death-receptor-independent activation of caspase 8. When HepG2 cells were transfected with ARK5 expression vector and subjected to several cell death stimuli, ARK5 was found to suppress cell death by glucose starvation, TRAIL, and TNF-alpha, but not by ultraviolet irradiation, camptothecin, or doxorubicin. Western blotting analysis revealed that both TRAIL and glucose starvation induced Bid cleavage and FLIP degradation following caspase 8 activation in a time-dependent manner, and ARK5 overexpression clearly delayed Bid cleavage, FLIP degradation, and caspase 8 activation. On the basis of the results of this study, we report that cell survival induced by ARK5 is, at least in part, due to inhibition of caspase 8 activation.
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PMID:ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation. 1367 56

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.
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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

TRAIL, a putative anticancer cytokine, induces extrinsic cell death by activating the caspase cascade directly (Type I cells) via the death-inducing signaling complex (DISC) or indirectly (Type II cells) by caspase-8 cleavage of Bid and activation of the mitochondrial cell death pathway. Cancer cells are characterized by their dependence on aerobic glycolysis, which, although inefficient in terms of ATP production, facilitates tumor metabolism. Our studies show that TRAIL-induced cell death is significantly affected by the metabolic status of the cell. Inhibiting glycolysis with 2-deoxyglucose potentiates TRAIL-induced cell death, whereas glucose deprivation can paradoxically inhibit apoptosis. These conflicting responses to glycolysis inhibition are modulated by the balance between the Akt and AMPK pathways and their subsequent downstream regulation of mTORC1. This results in marked changes in protein translation, in which the equilibrium between anti- and pro-apoptotic Bcl-2 family member proteins is decided by their individual degradation rates. This regulates the mitochondrial cell death pathway and alters its sensitivity not only to TRAIL, but to ABT-737, a Bcl-2 inhibitor. Taken together, our studies show that the sensitivity of cancer cells to apoptosis can be modulated by targeting their unique metabolism in order to enhance sensitivity to apoptotic agents.
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PMID:Glucose--a sweet way to die: metabolic switching modulates tumor cell death. 2298 94

While the anti-tumor efficacy of 2-deoxy-D-glucose (2-DG) is normally low in monotherapy, it may represent a valuable radio- and chemo-sensitizing agent. We here demonstrate that 2-10 mM 2-DG cooperates with arsenic trioxide (ATO) and other antitumor drugs to induce apoptosis in human myeloid leukemia cell lines. Using ATO and HL60 as drug and cell models, respectively, we observed that 2-DG/ATO combination activates the mitochondrial apoptotic pathway, as indicated by Bid-, and Bax-regulated cytochrome c and Omi/HtrA2 release, XIAP down-regulation, and caspase-9/-3 pathway activation. 2-DG neither causes oxidative stress nor increases ATO uptake, but causes inner mitochondria membrane permeabilization as well as moderate ATP depletion, which nevertheless do not satisfactorily explain the pro-apoptotic response. Surprisingly 2-DG causes cell line-specific decrease in LKB-1/AMPK phosphorylation/activation, and also causes Akt/mTOR/p70S6K and MEK/ERK activation, which is prevented by co-treatment with ATO. The use of kinase-specific pharmacologic inhibitors and/or siRNAs reveals that apoptosis is facilitated by AMPK inactivation and restrained by Akt and ERK activation, and that Akt and ERK activation mediates AMPK inhibition. Finally, 2-DG stimulates IGF-1R phosphorylation/activation, and co-treatment with IGF-1R inhibitor prevents 2-DG effects on Akt, ERK and AMPK, and facilitates 2-DG-provoked apoptosis. In summary 2-DG elicits IGF-1R-mediated AMPK inactivation and Akt and ERK activation, which facilitates or restrain apoptosis, respectively. 2-DG-provoked AMPK inactivation increases the apoptotic efficacy of ATO, while in turn ATO-provoked Akt and ERK inactivation may increase the efficacy of 2-DG as anti-tumor drug.
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PMID:2-Deoxy-D-glucose cooperates with arsenic trioxide to induce apoptosis in leukemia cells: involvement of IGF-1R-regulated Akt/mTOR, MEK/ERK and LKB-1/AMPK signaling pathways. 2304 Dec 29

Cancer, the leading causes of death worldwide, causes multiple metabolic and physiological alterations, leading to an unregulated proliferation of cells. The existing anticancer therapies are usually nonspecific with side effects and or are extremely expensive, thus hunt for better therapeutics is still on, specially efforts are made to look for naturally occurring molecules. Sea harbors several organisms which are unexplored for their biological potentials. Green macroalga genus, Caulerpa, is one such invaluable repository of bioactive metabolites like alkaloids, terpenoids, flavonoids, steroids and tannins with reported bioactivities against many diseases including cancer. Anti-cancerous metabolites of Caulerpa like caulerpenyne (Cyn), caulerpin, caulersin, and racemosin C, possess unique structural moieties and are known to exhibit distinct effects on cancer cells. Theses metabolites are reported to affect microtubule dynamics, unfolded protein response, mitochondrial health, cell cycle progression, metabolic and stress pathways by their cross-talk with signalling proteins like AMPK, GRP78, GADD153, Bid, Bax, AIF, Bcl2, P21, cyclin D, cyclin E, caspase 9, and PTP1B. Targeting of multiple cancer hallmarks by Caulerpa metabolites, with concomitant modulations of multiple signalling cascades, displays its multifactorial approach against cancer. Evaluation of anti-cancer properties of this genus is particularly important as Caulerpa species are widely edible and utilized in several delicacies in the coastal countries. This is the first review article providing a consolidated information about the role of Caulerpa in cancer with major contributing metabolites and plausible modulations in cancer signaling and prospects.
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PMID:Marine macroalga Caulerpa: role of its metabolites in modulating cancer signaling. 3098 Feb 71

Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK-caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.
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PMID:An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. 3207 35