Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.31 (AMP-activated protein kinase)
13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As tumors grow and invade beyond their homeostatic limits, the tumor cells are subjected to insufficient nutrient and oxygen supplies because of excessive demand for nutrition and oxygen, and insufficient vascularization. We therefore hypothesized that tolerance to nutrient deprivation as well as angiogenesis may be critical in some malignancies, including pancreatic cancers, which are seen to be a hypovascular tumor. In this study, we assessed the effect of AMP-activated protein kinase (AMPK), which plays a major role in protecting cells from metabolic stresses, on tumor biology under nutrient-deprived condition. Whereas hepatic cancer cells had mostly died within 48 h during glucose deprivation, most pancreatic cancer cells survived more than 48 h. The tolerance to glucose deprivation tended to correlate with the cells level of expression of AMPK alpha1 and alpha2. The introduction of AMPK antisense RNA expression vectors into pancreas cancer cell lines, PANC-1 and AsPC-1, significantly diminished their tolerance to glucose deprivation, and the stable transfection of AMPK antisense into PANC-1 cells inhibited tumor growth in nude mice. These findings indicate that AMPK expression contributes to tolerance to nutrient starvation in cancer cells. We propose AMPK as a new target for therapeutic strategies to suppress tumor growth and invasion.
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PMID:Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. 1220 20

AMP-activated protein kinases (AMPKs) are a class of serine/threonine protein kinases that are activated by an increase in intracellular AMP concentration. They are a sensitive indicator of cellular energy status and have been found to promote tumor cell survival during nutrient starvation. We recently identified a novel AMPK catalytic subunit family member, ARK5, whose activation is directly regulated by Akt, which, in turn, has been reported to be a key player in tumor malignancy. In this study, we attempted to determine whether ARK5 is involved in tumor malignancy under regulation by Akt. Matrigel invasion assays demonstrated that both overexpressed and endogenous ARK5 showed strong activity dependent on Akt. In addition, ARK5 expression induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 following new expression of membrane type 1 MMP (MT1-MMP), and the MT1-MMP expression induced by ARK5 was initiated by rapamycin-sensitive signaling. In nude mice, ARK5 expression was associated with a significant increase in tumor growth and significant suppression of necrosis in tumor tissue. Interestingly, only the ARK5-overexpressing PANC-1 cell line (P/ARK) tumor showed invasion and metastasis in nude mice, although Akt was activated in tumors derived from both P/ARK and its parental cell line. We report that a novel AMPK catalytic subunit family member, ARK5, plays a key role in tumor malignancy downstream of Akt.
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PMID:ARK5 is a tumor invasion-associated factor downstream of Akt signaling. 1506 Jan 71

Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non-small cell lung cancer (NSCLC) patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PI3-K) is coupled to the EGFR only in NSCLC cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PI3-K signaling in these cells. The central role PI3-K plays in cell survival suggests that a PI3-K inhibitor offers a strategy to increase the antitumor activity of EGFR inhibitors in resistant NSCL tumors that do not express ErbB-3. We show that PX-866, a PI3-K inhibitor with selectivity for p110alpha, potentiates the antitumor activity of gefitinib against even large A-549 NSCL xenografts giving complete tumor growth control in the early stages of treatment. A-549 xenograft phospho-Akt was inhibited by PX-866 but not by gefitinib. A major toxicity of PX-866 administration was hyperglycemia with decreased glucose tolerance, which was reversed upon cessation of treatment. The decreased glucose tolerance caused by PX-866 was insensitive to the AMP-activated protein kinase inhibitor metformin but reversed by insulin and by the peroxisome proliferator-activated receptor-gamma activator pioglitazone. Prolonged PX-866 administration also caused increased neutrophil counts. Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition.
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PMID:The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. 1617 26

The effect of the antidiabetic drug metformin on tumor growth was investigated using the paired isogenic colon cancer cell lines HCT116 p53(+/+) and HCT116 p53(-/-). Treatment with metformin selectively suppressed the tumor growth of HCT116 p53(-/-) xenografts. Following treatment with metformin, we detected increased apoptosis in p53(-/-) tumor sections and an enhanced susceptibility of p53(-/-) cells to undergo apoptosis in vitro when subject to nutrient deprivation. Metformin is proposed to function in diabetes treatment as an indirect activator of AMP-activated protein kinase (AMPK). Treatment with AICAR, another AMPK activator, also showed a selective ability to inhibit p53(-/-) tumor growth in vivo. In the presence of either of the two drugs, HCT116 p53(+/+) cells, but not HCT116 p53(-/-) cells, activated autophagy. A similar p53-dependent induction of autophagy was observed when nontransformed mouse embryo fibroblasts were treated. Treatment with either metformin or AICAR also led to enhanced fatty acid beta-oxidation in p53(+/+) MEFs, but not in p53(-/-) MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin treatment also suppressed mitochondrial electron transport. Metformin-treated cells compensated for this suppression of oxidative phosphorylation by increasing their rate of glycolysis in a p53-dependent manner. Together, these data suggest that metformin treatment forces a metabolic conversion that p53(-/-) cells are unable to execute. Thus, metformin is selectively toxic to p53-deficient cells and provides a potential mechanism for the reduced incidence of tumors observed in patients being treated with metformin.
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PMID:Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. 1763 85

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.
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PMID:The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. 1821 42

Cited research papers support the main hypothesis that selected publications supply sufficient information for a combined multi-level treatment strategy against cancer that will also strengthen the host. The three major elements of the proposal are: (A) metastasis being separate from tumor growth requires specific antimetastatic treatments. For this, manipulation of the composition of phospholipids will alter cellular charge characteristics which are instrumental in adhesion. (B) Formate metabolism is at the center of many activities that are controlling tumor growth. The rational and consequences of this are as follows. Supply of formate depends mainly on serine, and consumption on conversion to CO2 yielding needed NADPH. The remainder is used to complete IMP configuration with 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP). At homeostasis residual ZMP activates AMP-activated protein kinase (AMPK) to curb growth promoting phosphatidylinositol-3-kinase (PI3PK). Residual ZMP also activates the oxidation of choline to betaine supplying methyl groups needed for global methylation of DNA while increased oxidation of choline also alters cellular phospholipid composition (refer to metastasis). At low formate level, increased accumulated ZMP becomes pyrophosporylated to ZTP. AMPK activation shifts to PI3PK activity for insulin action restoring formate supplied by serine derived from glycolysis. Increased NADPH-generating glucose-6-phosphate dehydrogenase is diminishing NADP+ required for dehydrogenation of formate. This is restoring the formate balance while lowering ZMP levels to that of homeostasis. Evidence suggests that transformed cells exceed up-regulation of formate thus suppressing all ZMP accumulations resulting in limited AMPK activation, cessation of choline oxidation to betaine and loss of global methylation of DNA. This scenario appears to be tied to tumor survival, a state that could be altered by metabolic interventions using mild agents as described in the research reports cited. (C) Because of a preponderance of pyrimidines in cancer supporting UTP requiring immune evasion, exogenous IMP may offset this imbalance and thus hinder tumor anti-immune activities while strengthen host immune functions. For studies to confirm the proposal, the overall expected result is that a combined administration of all these agents cited here will outperform any single agent considered so far for anticancer treatment.
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PMID:The need for a multi-level biochemical approach to defeat cancer that will also support the host. 1875 5

Caloric restriction has long been recognized as an extremely effective cancer preventive. Current population demographics suggest that caloric excess and obesity will lead to increased cancer incidence, underscoring the need to elucidate the molecular mechanisms that couple dysregulated energy homeostasis to aberrant cell growth. The AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status, largely studied for its importance in metabolic regulation. AMPK also controls processes relevant to tumor development, including cell cycle progression, protein synthesis, cell growth, and survival. Several tumor suppressors impinge on AMPK signaling, and activation of the kinase inhibits tumor growth. However, AMPK can also promote cancer in some settings, necessitating a more complete understanding of the complexities of this signaling network. Because dysregulated energy balance is a nexus for multiple chronic diseases of aging, drugs that target these pathways may find broad utility in aging populations.
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PMID:Energy homeostasis and cancer prevention: the AMP-activated protein kinase. 1933 31

Triple negative (TN) breast cancer is more frequent in women who are obese or have type II diabetes, as well as young women of color. These cancers do not express receptors for the steroid hormones estrogen or progesterone, or the type II receptor tyrosine kinase (RTK) Her-2 but do have upregulation of basal cytokeratins and the epidermal growth factor receptor (EGFR). These data suggest that aberrations of glucose and fatty acid metabolism, signaling through EGFR and genetic factors may promote the development of TN cancers. The anti-type II diabetes drug metformin has been associated with a decreased incidence of breast cancer, although the specific molecular subtypes that may be reduced by metformin have not been reported. Our data indicates that metformin has unique anti-TN breast cancer effects both in vitro and in vivo. It inhibits cell proliferation (with partial S phase arrest), colony formation and induces apoptosis via activation of the intrinsic and extrinsic signaling pathways only in TN breast cancer cell lines. At the molecular level, metformin increases P-AMPK, reduces P-EGFR, EGFR, P-MAPK, P-Src, cyclin D1 and cyclin E (but not cyclin A or B, p27 or p21), and induces PARP cleavage in a dose- and time-dependent manner. These data are in stark contrast to our previously published biological and molecular effects of metformin on luminal A and B, or Her-2 type breast cancer cells. Nude mice bearing tumor xenografts of the TN line MDA-MB-231, treated with metformin, show significant reductions in tumor growth (p = 0.0066) and cell proliferation (p = 0.0021) as compared to untreated controls. Metformin pre-treatment, before injection of MDA-MB-231 cells, results in a significant decrease in tumor outgrowth and incidence. Given the unique anti-cancer activity of metformin against TN disease, both in vitro and in vivo, it should be explored as a therapeutic agent against this aggressive form of breast cancer.
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PMID:Metformin induces unique biological and molecular responses in triple negative breast cancer cells. 1971 81

Hypoxia-inducible factor-1alpha (HIF-1alpha) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1alpha, and the augmented HIF-1alpha activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1alpha activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1alpha expression through an increase in ubiquitination, thereby accelerating HIF-1alpha degradation and inhibiting HIF-1alpha-dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1alpha activity. CA-S6K1 overexpression reversed HIF-1alpha inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1alpha was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-alpha to restore the ability of insulin to increase HIF-1alpha against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H(2)O(2) production, thereby preventing H(2)O(2)-enhanced HIF-1alpha expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1alpha activity and HIF-1alpha-dependent tumor growth, which may result from a decrease in HIF-1alpha stability through S6K1 inhibition in combination with an H(2)O(2)-scavenging effect.
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PMID:Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1alpha activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect. 1978 18

Conjugated linoleic acid (CLA) inhibits tumorigenesis and tumor growth in most model systems, an effect mediated in part by its pro-apoptotic activity. We previously showed that trans-10,cis-12 CLA induced apoptosis of p53-mutant TM4t mouse mammary tumor cells through both mitochondrial and endoplasmic reticulum stress pathways. In the current study, we investigated the role of AMP-activated protein kinase (AMPK), a key player in fatty acid metabolism, in CLA-induced apoptosis in TM4t cells. We found that t10,c12-CLA increased phosphorylation of AMPK, and that CLA-induced apoptosis was enhanced by the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and inhibited by the AMPK inhibitor compound C. The increased AMPK activity was not due to nutrient/energy depletion since ATP levels did not change in CLA-treated cells, and knockdown of the upstream kinase LKB1 did not affect its activity. Furthermore, our data do not demonstrate a role for the AMPK-modulated mTOR pathway in CLA-induced apoptosis. Although CLA decreased mTOR levels, activity was only modestly decreased. Moreover, rapamycin, which completely blocked the activity of mTORC1 and mTORC2, did not induce apoptosis, and attenuated rather than enhanced CLA-induced apoptosis. Instead, the data suggest that CLA-induced apoptosis is mediated by the AMPK-p38 MAPK-Bim pathway: CLA-induced phosphorylation of AMPK and p38 MAPK, and increased expression of Bim, occurred with a similar time course as apoptosis; phosphorylation of p38 MAPK was blocked by compound C; the increased Bim expression was blocked by p38 MAPK siRNA; CLA-induced apoptosis was attenuated by the p38 inhibitor SB-203580 and by siRNAs directed against p38 MAPK or Bim.
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PMID:Activation of the AMP-activated protein kinase-p38 MAP kinase pathway mediates apoptosis induced by conjugated linoleic acid in p53-mutant mouse mammary tumor cells. 1993 74


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