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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Here we show that curcumin inhibited growth of rhabdomyosarcoma cells (Rh1 and Rh30) (IC50 = 2-5 microM) and arrested cells in G1 phase of the cell cycle. Curcumin also induced apoptosis and inhibited the basal or type I insulin-like growth factor-induced motility of the cells. At physiological concentrations (2.5 microM), curcumin rapidly inhibited phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a panel of cell lines (Rh1, Rh30, DU145, MCF-7 and Hela). Curcumin also inhibited phosphorylation of Akt in the cells, but only at high concentrations (>40 microM). The data suggest that curcumin may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells.
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PMID:Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. 1655 Jun 6

The oncoprotein MDM2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and p53-independent activities. We have identified curcumin, which has previously been shown to have anticancer activity, as an inhibitor of MDM2 expression. Curcumin down-regulates MDM2, independent of p53. In a human prostate cancer cell lines PC3 (p53(null)), curcumin reduced MDM2 protein and mRNA in a dose- and time-dependent manner, and enhanced the expression of the tumor suppressor p21(Waf1/CIP1). The inhibitory effects occur at the transcriptional level and seem to involve the phosphatidylinositol 3-kinase/mammalian target of rapamycin/erythroblastosis virus transcription factor 2 pathway. Curcumin induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM2 overexpression and knockdown reduced these effects. Curcumin also inhibited the growth of these cells and enhanced the cytotoxic effects of gemcitabine. When it was administered to tumor-bearing nude mice, curcumin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of MDM2. Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of action that may be essential for its chemopreventive and chemotherapeutic effects. Our observations help to elucidate the process by which mitogens up-regulate MDM2, independent of p53, and identify a mechanism by which curcumin functions as an anticancer agent.
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PMID:Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. 1733 26

Autophagy is a response of cancer cells to various anticancer therapies. It is designated as programmed cell death type II and characterized by the formation of autophagic vacuoles in the cytoplasm. The Akt/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathways are two major pathways that regulate autophagy induced by nutrient starvation. These pathways are also frequently associated with oncogenesis in a variety of cancer cell types, including malignant gliomas. However, few studies have examined both of these signal pathways in the context of anticancer therapy-induced autophagy in cancer cells, and the effect of autophagy on cell death remains unclear. Here, we examined the anticancer efficacy and mechanisms of curcumin, a natural compound with low toxicity in normal cells, in U87-MG and U373-MG malignant glioma cells. Curcumin induced G(2)/M arrest and nonapoptotic autophagic cell death in both cell types. It inhibited the Akt/mTOR/p70S6K pathway and activated the ERK1/2 pathway, resulting in induction of autophagy. It is interesting that activation of the Akt pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the ERK1/2 pathway inhibited curcumin-induced autophagy and induced apoptosis, thus resulting in enhanced cytotoxicity. These results imply that the effect of autophagy on cell death may be pathway-specific. In the subcutaneous xenograft model of U87-MG cells, curcumin inhibited tumor growth significantly (P < 0.05) and induced autophagy. These results suggest that curcumin has high anticancer efficacy in vitro and in vivo by inducing autophagy and warrant further investigation toward possible clinical application in patients with malignant glioma.
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PMID:Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. 1739 90

Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase, and inducible nitric oxide synthase (iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF-KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC, mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c-fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway.
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PMID:Molecular targets of curcumin. 1756 14

Curcumin has a potent anticancer effect and is a promising new therapeutic strategy. We previously demonstrated that curcumin induced non-apoptotic autophagic cell death in malignant glioma cells in vitro and in vivo. This compound inhibited the Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase pathway and activated the extracellular signal-regulated kinases 1/2 thereby inducing autophagy. Interestingly, activation of the first pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the latter pathway inhibited curcumin-induced autophagy and induced apoptosis, thus augmenting the cytotoxicity of curcumin. These results imply that these two autophagic pathways have opposite effects on curcumin's cytotoxicity. However, inhibition of nuclear factor kappaB, which is the main target of curcumin for its anticancer effect, was not observed in malignant glioma cells. These results suggest that autophagy but not nuclear factor kappaB plays a central role in curcumin anticancer therapy and warrant further investigation toward application in patients with malignant gliomas. Here, we discuss the therapeutic role of two autophagic pathways influenced by curcumin.
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PMID:Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. 1778 26

Akt/mammalian target of rapamycin (mTOR) signaling plays an important role in tumorigenesis and is dysregulated in many tumors, especially metastatic prostate cancers. Curcumin has been shown to effectively prevent or inhibit prostate cancer in vivo and inhibit Akt/mTOR signaling in vitro, but the mechanism(s) remains unclear. Here, we show that curcumin concentration- and time-dependently inhibited the phosphorylation of Akt, mTOR, and their downstream substrates in human prostate cancer PC-3 cells, and this inhibitory effect acts downstream of phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase 1. Overexpression of constitutively activated Akt or disruption of TSC1-TSC2 complex by small interfering RNA or gene knockout only partially restored curcumin-mediated inhibition of mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin-mediated inhibition of Akt/mTOR signaling. Curcumin also activated 5'-AMP-activated protein kinase and mitogen-activated protein kinases; however, inhibition of these kinases failed to rescue the inhibition by curcumin. Finally, it was shown that the inhibition of Akt/mTOR signaling by curcumin is resulted from calyculin A-sensitive protein phosphatase-dependent dephosphorylation. Our study reveals the profound effects of curcumin on the Akt/mTOR signaling network in PC-3 cells and provides new mechanisms for the anticancer effects of curcumin.
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PMID:Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. 1879 Jul 44

Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKalpha. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor.
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PMID:Curcumin disrupts the Mammalian target of rapamycin-raptor complex. 1917 85

Curcumin is a phytochemical isolated from the rhizome of turmeric. Recent reports have shown curcumin to have antioxidant, anti-inflammatory and anti-tumor properties as well as affecting the 5'-AMP activated protein kinase (AMPK), mTOR and STAT-3 signaling pathways. We provide evidence that curcumin acts as an uncoupler. Well-established biochemical techniques were performed on isolated rat liver mitochondria in measuring oxygen consumption, F(0)F(1)-ATPase activity and ATP biosynthesis. Curcumin displays all the characteristics typical of classical uncouplers like fccP and 2,4-dinitrophenol. In addition, at concentrations higher than 50 microM, curcumin was found to inhibit mitochondrial respiration which is a characteristic feature of inhibitory uncouplers. As a protonophoric uncoupler and as an activator of F(0)F(1)-ATPase, curcumin causes a decrease in ATP biosynthesis in rat liver mitochondria. The resulting change in ATP:AMP could disrupt the phosphorylation status of the cell; this provides a possible mechanism for its activation of AMPK and its downstream mTOR and STAT-3 signaling.
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PMID:Uncoupling of oxidative phosphorylation by curcumin: implication of its cellular mechanism of action. 1971 74

Radiation therapy is an essential modality in the treatment of colorectal cancers. Radiation exerts an antiangiogenic effect on tumors, inhibiting endothelial proliferation and survival in the tumor microvasculature. However, damage from low levels of irradiation can induce a paradoxical effect, stimulating survival in endothelial cells. We used human intestinal microvascular endothelial cells (HIMEC) to define effects of radiation on these gut-specific endothelial cells. Low-level irradiation (1-5 Gy) activates NF-kappaB and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in cell cycle reentry and cell survival in HIMEC. A downstream target of PI3K/Akt is mammalian target of rapamycin (mTOR), which contributes to endothelial proliferation and angiogenesis. The aim of this study was to investigate the signaling molecules involved in the radiosensitizing effects of curcumin on HIMEC subjected to low levels of irradiation. We have demonstrated that exposure of HIMEC to low levels of irradiation induced Akt and mTOR phosphorylation, which was attenuated by curcumin, rapamycin, LY294002, and mTOR small interference RNA (siRNA). Activation of NF-kappaB by low levels of irradiation was inhibited by curcumin, SN-50, and mTOR siRNA. Curcumin also induced apoptosis by induction of caspase-3 cleavage in irradiated HIMEC. In conclusion, curcumin significantly inhibited NF-kappaB and attenuated the effect of irradiation-induced prosurvival signaling through the PI3K/Akt/mTOR and NF-kappaB pathways in these gut-specific endothelial cells. Curcumin may be a potential radiosensitizing agent for enhanced antiangiogenic effect in colorectal cancer radiation therapy.
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PMID:Modulatory effect of curcumin on survival of irradiated human intestinal microvascular endothelial cells: role of Akt/mTOR and NF-{kappa}B. 2029 3

Curcumin has been verified as an anti-cancer compound via multiple molecular targets. Its effective mechanisms include cell cycle arrest, inducing apoptosis, suppressing oncogenes, and enhancing tumor suppressor genes. The resistance of cells to chemotherapy, however, derives from the variable genetic aberration of cancer cells. Consequently, the core signaling pathways of glioblastoma have been explored to evaluate the efficacy of curcumin in proceeding through mutated genes in those pathways. In this study, the efficacy of curcumin was investigated in DBTRG cells. The cytotoxic ability was detected with MTT assay, and the influence of the cell cycle was checked with flow cytometry. The influence of the core signaling pathways was evaluated by Western blotting through the predominantly mutated proteins which included p53, p21, and cdc2 in the p53 pathway, CDKN2A/p16 and RB in the RB pathway, and EGFR, mTOR, Ras, PTEN, and Akt in the RTK-Ras-PI3K pathway. In addition, the apoptotic effect was determined by apoptosis-associated proteins Bcl-2, Bax, and caspase 3. Curcumin exhibits superior cytotoxicity on glioblastoma in a dose- and time-dependent manner in the MTT assay. In the core signaling pathways of glioblastoma, curcumin either significantly influences the p53 pathway by enhancing p53 and p21 and suppressing cdc2 or significantly inhibits the RB pathway by enhancing CDKN2A/p16 and suppressing phosphorylated RB. In the apoptotic pathway, the Bax and caspase 3 are significantly suppressed by curcumin and the Giemsa stain elucidates apoptotic features of DBTRG cells as well. In conclusion, curcumin appears to be an effective anti-glioblastoma drug through inhibition of the two core signaling pathways and promotion of the apoptotic pathway.
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PMID:The anti-cancer efficacy of curcumin scrutinized through core signaling pathways in glioblastoma. 2059 1


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