Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mantle cell lymphoma (MCL) is a clinically aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) and overexpression of cyclin D1. A high proportion of MCL tumors harbor wild-type (wt) and potentially functional p53 gene. We show here that stabilization and activation of wt-p53 using a recently developed potent MDM2 inhibitor, nutlin 3A, results in significant p53-dependent G1-S cell cycle arrest and apoptosis in MCL cells through regulation of p53 target genes. As mTOR signaling is activated in MCL and may control cyclin D1 levels, we show that p53 activation may downregulate the AKT/mTOR pathway through a mechanism involving AMP kinase (AMPK). Despite the non-genotoxic mode of nutlin 3A treatment, we show evidence that stabilization of p53 is associated with its phosphorylation at serine 15 residue and activation of AMPK. Stimulation of AMPK kinase activity using AICAR inhibits phosphorylation of critical downstream effectors of mTOR signaling, such as 4E-BP1 and rpS6. Pharmacologic inhibition of AMPK using compound C in nutlin-3A-treated MCL cells harboring wt-p53 did not affect the level of (ser15)p-p53, suggesting that the (ser15)p-p53 --> AMPK is the direction involved in the p53/AMPK/mTOR cross talk. These data establish a p53 --> AMPK --> mTOR mechanism in MCL and uncover a novel biologic effect of potent MDM2 inhibitors in preclinical models of MCL.
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PMID:Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. 1922 36

AMP-activated protein kinase (AMPK) is a critical energy-balancing sensor in the regulation of cellular metabolism in response to external stimuli. Emerging evidence has suggested that AMPK is a potential therapeutic target for human cancers. AICAR, one of the pharmacological AMPK activators, has been widely used to suppress cancer cell growth through activation of LKB1, an upstream kinase of AMPK. However, frequent mutations and deletions of LKB1 found in some cancer cells limit the application of AICAR as an efficient therapeutic drug. Here we show that an alternative pharmacological AMPK activator, A23187, was able to inhibit cervical cancer cell growth through activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta, another upstream kinase of AMPK. Using cervical cancer cell models, we found that HeLa (LKB1-deficient cell) responded less to the anti-proliferative effect exerted by AICAR treatment (p < 0.001) compared with CaSki and C41 (LKB1-expressing cells). Conversely, the anti-proliferative effect was increased significantly in HeLa but not in CaSki and C41 cells under treatment by A23187 (p < 0.001). Moreover, co-treatment of AICAR and A23187 was able to further enhance the inhibitory effect on cell growth of Hela, CaSki and C41 cells. Notably, both AICAR and A23187 exerted the anti-proliferative effect on cervical cancer cells by suppressing AMPK/mTOR signalling activity. These data suggest that A23187 could be an alternative potential therapeutic drug used for anti-proliferation in LKB1-deficient cancer cells.
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PMID:Inhibition of cervical cancer cell growth through activation of upstream kinases of AMP-activated protein kinase. 1940 87

The EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by (18)fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.
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PMID:The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. 1962 24

Stimulated by energetic stress, AMP-activated protein kinase (AMPK) controls several cellular functions. It was discovered here that infection of Vero cells with avian reovirus (ARV) upregulated AMPK and mitogen-activated protein kinase (MAPK) p38 phosphorylation in a time- and dose-dependent manner. Being an energy status sensor, AMPK is potentially an upstream regulator of MAPK p38. Treatment with 5-amino-4-imidazolecarboxamide ribose (AICAR), a well-known activator of AMPK, induced phosphorylation of MAPK p38. Unlike AICAR, wortmannin or rapamycin did not induce phosphorylation of MAPK p38, suggesting that mTOR inhibition is not a determining factor in MAPK p38 phosphorylation. Inhibition of AMPK by compound C antagonized the effect of AICAR on MAPK p38 in Vero cells. Specific inhibition of AMPK by small interfering RNA or compound C also suppressed ARV-induced phosphorylation of MAPK kinase (MKK) 3/6 and MAPK p38 in Vero and DF-1 cells, thereby providing a link between AMPK signalling and the MAPK p38 pathway. The mechanism of ARV-enhanced phosphorylation of MKK 3/6 and MAPK p38 in cells was not merely due to glucose deprivation, a probable activator of AMPK. In the current study, direct inhibition of MAPK p38 by SB202190 decreased the level of ARV-induced syncytium formation in Vero and DF-1 cells, and decreased the protein levels of ARV sigma A and sigma C and the progeny titre of ARV, suggesting that activation of MAPK p38 is beneficial for ARV replication. Taken together, these results suggested that AMPK could facilitate MKK 3/6 and MAPK p38 signalling that is beneficial for ARV replication. Although well studied in energy metabolism, this study provides evidence for the first time that AMPK plays a role in modulating ARV and host-cell interaction.
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PMID:AMP-activated protein kinase facilitates avian reovirus to induce mitogen-activated protein kinase (MAPK) p38 and MAPK kinase 3/6 signalling that is beneficial for virus replication. 1965 61

Globular adiponectin (gAd) induces the generation of reactive oxygen species (ROS) and nitric oxide (NO) in the murine macrophage cell line RAW 264. This study investigated the role of the mammalian target of rapamycin (mTOR) in gAd-induced ROS and NO generation. gAd stimulation induced phosphorylation of mTOR, which peaked at 20 min and dissolved rapidly. Inhibition of phosphatidylinositol 3-kinase activity with wortmannin suppressed gAd-induced phosphorylation of Akt and mTOR. Administration of rapamycin partially reduced gAd-induced generation of intracellular and mitochondrial ROS, but not release of NO. To further confirm the role of mTOR in gAd stimulation, the effect of the activators of AMP-activated protein kinase (AMPK) on gAd-induced mTOR phosphorylation was examined. Pre-treatment with three kinds of AMPK activators, AICAR, 2-deoxy-D-glucose and A-769662, suppressed gAd-induced mTOR phosphorylation. Furthermore, these AMPK activators significantly reduced gAd-evoked intracellular and mitochondrial ROS generation and NO release.
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PMID:Involvement of mTOR in globular adiponectin-induced generation of reactive oxygen species. 1988 50

5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), an analog of AMP, is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy change. We studied the effects of AICAR on the growth of retinoblastoma cell lines (Y79, WERI, and RB143). AICAR inhibited Rb cell growth, induced apoptosis and S-phase cell cycle arrest, and led to activation of AMPK. These effects were abolished by treatment with dypiridamole, an inhibitor that blocks entrance of AICAR into cells. Treatment with the adenosine kinase inhibitor 5-iodotubericidin to inhibit the conversion of AICAR to ZMP (the direct activator of AMPK) reversed most of the growth-inhibiting effects of AICAR, indicating that some of the antiproliferative effects of AICAR are mediated through AMPK activation. In addition, AICAR treatment was associated with inhibition of the mammalian target of rapamycin pathway, decreased phosphorylation of ribosomal protein-S6 and 4E-BP1, down-regulation of cyclins A and E, and decreased expression of p21. Our results indicate that AICAR-induced activation of AMPK inhibits retinoblastoma cell growth. This is one of the first descriptions of a nonchemotherapeutic drug with low toxicity that may be effective in treating Rb patients.
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PMID:Retinoblastoma cells are inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. 2037 23

Extensive studies over the years have shown that the AMP-activated kinase (AMPK) exhibits negative regulatory effects on the activation of the mammalian target of rapamycin (mTOR) signaling cascade. We examined the potential involvement of AMPK in the regulation of growth and survival of malignant melanoma cells. In studies using the AMPK activators AICAR or metformin, we found potent inhibitory effects of AMPK activity on the growth of SK-MEL-2 and SK-MEL-28 malignant melanoma cells. Induction of AMPK activity was also associated with inhibition of the ability of melanoma cells to form colonies in an anchorage-independent manner in soft agar, suggesting an important role of the pathway in the control of malignant melanoma tumorigenesis. Furthermore, AICAR-treatment resulted in malignant melanoma cell death and such induction of apoptosis was further enhanced by concomitant statin-treatment. Taken together, our results provide evidence for potent inhibitory effects of AMPK on malignant melanoma cell growth and survival and raise the potential of AMPK manipulation as a novel future approach for the treatment of malignant melanoma.
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PMID:AMP-activated kinase (AMPK)-generated signals in malignant melanoma cell growth and survival. 2059 46

The melanocortin signaling system is integral in regulating energy homeostasis. The melanocortin-4 receptor (MC4R) activates several signaling pathways in performance of this function. The effect of MC4R on insulin-stimulated mammalian target of rapamycin (mTOR), a cellular energy sensor, signaling was investigated. The GT1-1 cell line which expresses MC4R expression was utilized. mTOR signaling was measured by Western blotting analysis using Phospho-mTOR (Ser2448) antibody. NDP-MSH dose-dependently enhanced insulin-stimulated mTOR phosphorylation. The MC4R antagonist SHU9119 blocked this effect, demonstrating specificity. The protein kinase A - cyclic AMP pathway and the MAP kinase pathway were not involved in NDP-MSH actions on insulin-stimulated mTOR phosphorylation. In contrast, the AMP-activated protein kinase agonist, AICAR, attenuated this effect. MC4R activation potentiates insulin-stimulated mTOR signaling via the AMPK pathway.
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PMID:Melanocortin-4 receptor activation promotes insulin-stimulated mTOR signaling. 2060 72

New chemotherapy-enhancing strategies are needed for better cancer therapy. Previous studies suggest that exogenous cell-permeable C6 ceramide may be a useful adjunct to the anti-tumor effects of chemotherapeutic agents (such as Taxol) against multiple cancers. Here we demonstrate that exogenous cell-permeable C6 ceramide largely sensitizes multiple progressive cancer cell lines to Doxorubicin-induced cell death and apoptosis. We found for the first time that Doxorubicin induces AMP-activated protein kinase (AMPK) activation in a reactive oxygen species-dependent manner. Activation of AMPK contributes to Doxorubicin-induced cancer cell death and apoptosis. Inhibition of AMPK by small interfering RNA knockdown or a pharmacological inhibitor reduces Doxorubicin-induced cancer cell apoptosis, whereas AMPK activator AICAR enhances it. Importantly, we found that C6 ceramide largely enhances Doxorubicin-induced activation of AMPK, which leads to mTOR complex 1 inhibition and chemo-sensitization. Our data suggest that the combination of C6 ceramide with traditional chemotherapy drugs such as Doxorubicin may have the potential to be used as a new therapeutic intervention against multiple cancers.
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PMID:Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition. 2080 18

AMPK is a cellular energy sensor that negatively regulates the mTOR signaling pathway. As mTOR plays critical roles in cell growth and tumorigenesis of renal cell carcinoma (RCC), we examined whether exogenous induction of AMPK activity exhibits inhibitory effects on growth and survival of renal cell carcinoma cells. Activation of AMPK by AICAR resulted in potent suppressive effects on RCC growth, while combinations of AICAR with statins were potent inducers of apoptosis in such cells. The effects of AICAR resulted from inhibition of mTOR and its effectors, resulting from induction of AMPK activity. Similar results on RCC cell growth were obtained when combinations of metformin with statins were examined. Importantly, studies to examine the effects of AICAR or metformin, alone or in combinations with statins, on anchorage-independent growth demonstrated potent suppressive effects on RCC tumorigenicity in vitro. Altogether, our studies demonstrate that AMPK plays critical regulatory roles in the regulation of growth of RCC cells and raise the prospect of future use of AMPK activators in the treatment of renal cell carcinoma in humans.
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PMID:AMPK as a therapeutic target in renal cell carcinoma. 2105 16


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