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)

An early event of cell migration is characterized as the rapid reorganization of the actin cytoskeleton. Recently, we have demonstrated that rapamycin inhibits tumor cell motility. To understand the underlying mechanism, this study was set to determine whether rapamycin inhibition of cell motility is related to its prevention of F-actin reorganization. We found that rapamycin prevented type I insulin-like growth factor (IGF-I)-stimulated F-actin reorganization in human rhabdomyosarcoma (Rh30), Ewing sarcoma (Rh1), glioblastoma (U-373) and prostate carcinoma (PC-3) cells, and concurrently inhibited phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK), paxillin and p130(Cas) in the cells. The effect of rapamycin was blocked by expression of a rapamycin-resistant mutant of mTOR (mTORrr), but not a kinase-dead mTORrr. Downregulation of raptor mimicked the effect of rapamycin. Cells infected with a recombinant adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6 kinase 1 (S6K1) conferred to resistance to rapamycin. Further, IGF-I failed to stimulate F-actin reorganization and phosphorylation of the focal adhesion proteins in the S6K1-downregulated cells. Expression of constitutively hypophosphorylated eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1-5A) inhibited IGF-I-stimulated F-actin reorganization, but did not alter the cellular protein or phosphorylation levels of the focal adhesion proteins. The results suggest that rapamycin inhibits IGF-I-induced F-actin reorganization and phosphorylation of the focal adhesion proteins by disruption of mTOR-raptor complex. Both S6K1 and 4E-BP1 pathways, mediated by the mTOR-raptor complex, are involved in the regulation of IGF-I-stimulated F-actin reorganization, but only the former controls IGF-I-stimulated phosphorylation of the focal adhesion proteins.
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PMID:Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. 1850 40

The pathways that allow quiescent disseminated cancer cells to survive during prolonged dormancy periods are unknown. Here, we identify the transcription factor ATF6alpha as a pivotal survival factor for quiescent but not proliferative squamous carcinoma cells. ATF6alpha is essential for the adaptation of dormant cells to chemotherapy, nutritional stress, and, most importantly, the in vivo microenvironment. Mechanism analysis showed that MKK6 and p38alpha/beta contribute to regulating nuclear translocation and transcriptional activation of ATF6alpha in dormant cancer cells. Downstream, ATF6alpha induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt. Down-regulation of ATF6alpha or Rheb reverted dormant tumor cell resistance to rapamycin and induced pronounced killing only of dormant cancer cells in vivo. Knocking down ATF6alpha also prolonged the survival of nude mice bearing dormant tumor cells. Targeting survival signaling by the ATF6alpha-Rheb-mTOR pathway in dormant tumor cells may favor the eradication of residual disease during dormancy periods.
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PMID:ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. 1865 Mar 80

Areca nut (AN) is recognized as a human carcinogen; however, few studies of the cytotoxic effects of AN ingredients on cells have been reported. In Taiwan, AN, lime and inflorescence of Piper betle are the common components of betel quid (BQ). We recently noticed that extract of AN (ANE), but not those of lime and inflorescence of Piper betle, induces rounding cell morphology and nuclear shrinkage in different types of carcinoma cells. In this study, the rounding cell activity was first traced to the partially purified >or=10 kDa fraction (ANE >or= 10 K) and subsequently to the 30-100 kDa fraction (ANE 30-100 K). ANE and ANE >or=10 K stimulated nuclear shrinkage (P < 0.001 in both cases) and the clearance of the cytoplasm. ANE, ANE >or= 10 K, and ANE 30-100 K induced the cleavage of LC3-I (P < 0.05, 0.01, and 0.05, respectively) and the emergence of autophagic vacuoles (AVs) and acidic vesicles. On the other hand, arecoline (Are, the major alkaloid of AN) triggered caspase-3 activation, peri-nuclear chromatin condensation, and micronucleation. Meanwhile, ANE 30-100 K, but not Are, inhibited the phosphorylation of the mammalian target of rapamycin (mTOR)-Ser(2448). In conclusion, this study demonstrates that different AN ingredients exerting differential impact on mTOR-Ser(2448) phosphorylation are capable of triggering apoptosis and autophagy.
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PMID:Arecoline and the 30-100 kDa fraction of areca nut extract differentially regulate mTOR and respectively induce apoptosis and autophagy: a pilot study. 1866 45

Little is known about lung carcinoma epidermal growth factor (EGF) kinase pathway signaling within the context of the tissue microenvironment. We quantitatively profiled the phosphorylation and abundance of signal pathway proteins relevant to the EGF receptor within laser capture microdissected untreated, human non-small cell lung cancer (NSCLC) (n = 25) of known epidermal growth factor receptor (EGFR) tyrosine kinase domain mutation status. We measured six phosphorylation sites on EGFR to evaluate whether EGFR mutation status in vivo was associated with the coordinated phosphorylation of specific multiple phosphorylation sites on the EGFR and downstream proteins. Reverse phase protein array quantitation of NSCLC revealed simultaneous increased phosphorylation of EGFR residues Tyr-1148 (p < 0.044) and Tyr-1068 (p < 0.026) and decreased phosphorylation of EGFR Tyr-1045 (p < 0.002), HER2 Tyr-1248 (p < 0.015), IRS-1 Ser-612 (p < 0.001), and SMAD Ser-465/467 (p < 0.011) across all classes of mutated EGFR patient samples compared with wild type. To explore which subset of correlations was influenced by ligand induction versus an intrinsic phenotype of the EGFR mutants, we profiled the time course of 115 cellular signal proteins for EGF ligand-stimulated (three dosages) NSCLC mutant and wild type cultured cell lines. EGFR mutant cell lines (H1975 L858R) displayed a pattern of EGFR Tyr-1045 and HER2 Tyr-1248 phosphorylation similar to that found in tissue. Persistence of phosphorylation for AKT Ser-473 following ligand stimulation was found for the mutant. These data suggest that a higher proportion of the EGFR mutant carcinoma cells may exhibit activation of the phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (MTOR) pathway through Tyr-1148 and Tyr-1068 and suppression of IRS-1 Ser-612, altered heterodimerization with ERBB2, reduced response to transforming growth factor beta suppression, and reduced ubiquitination/degradation of the EGFR through EGFR Tyr-1045, thus providing a survival advantage. This is the first comparison of multiple, site-specific phosphoproteins with the EGFR tyrosine kinase domain mutation status in vivo.
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PMID:Laser capture microdissection and protein microarray analysis of human non-small cell lung cancer: differential epidermal growth factor receptor (EGPR) phosphorylation events associated with mutated EGFR compared with wild type. 1868 33

Angiogenesis is an important factor for cancer development and progression in humans. Hereditary and sporadic renal cell carcinoma are characterized by inactivation of the Von-Hippel Lindau (VHL) gene, which results in hyperactivity of the hypoxia-inducible factor-a (HIFa). As a consequence, there is a production of angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The activity of these factors is associated with oncogenesis, growth, and metastatic potential of renal-cell carcinoma. These data indicate that angiogenic factors are the promising therapeutic targets in this disease. Surgery can cure the patients with renal cancer if disease is diagnosed at an early stage. On the contrary, inoperable or metastatic disease is not curable. Until recently, the only drugs approved for the treatment of advanced disease were the cytokines, interferon, and interleukin. Nevertheless, only a minority of patients (about 15%) would benefited from this treatment, while the toxicity was considerable. During the last 5 years a new era of biological agents, with considerable activity has been developed and tested in clinical trials and (some of them) have been approved in USA and Europe. These agents are: Sunitinib, Bevacizumab, Sorafenib and Temserolimus. Bevacizumab is an anti-VEGF monoclonal antibody, Sunitinib and Sorafenib are multi- tyrosine kinase inhibitors (TKIs), while Temserolimus is a mTOR inhibitor. The common these in their development is the inhibition of angiogenesis, which may explain their significant activity in renal-cell carcinoma. All the agents have been proven more effective than the interferon as first or second-line treatment. This review will focus in these recent developments and the intense continuing clinical research in this field.
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PMID:Targeting angiogenesis in renal cell carcinoma. 1869 Aug 41

Dysregulated angiogenesis and high tumor vasculature permeability, two vascular endothelial growth factor (VEGF)-mediated processes and hallmarks of human tumors, are in part phosphatidylinositol 3-kinase (PI3K) dependent. NVP-BEZ235, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, was found to potently inhibit VEGF-induced cell proliferation and survival in vitro and VEGF-induced angiogenesis in vivo as shown with s.c. VEGF-impregnated agar chambers. Moreover, the compound strongly inhibited microvessel permeability both in normal tissue and in BN472 mammary carcinoma grown orthotopically in syngeneic rats. Similarly, tumor interstitial fluid pressure, a phenomenon that is also dependent of tumor permeability, was significantly reduced by NVP-BEZ235 in a dose-dependent manner on p.o. administration. Because RAD001, a specific mTOR allosteric inhibitor, was ineffective in the preceding experiments, we concluded that the effects observed for NVP-BEZ235 are in part driven by PI3K target modulation. Hence, tumor vasculature reduction was correlated with full blockade of endothelial nitric oxide (NO) synthase, a PI3K/Akt-dependent but mTORC1-independent effector involved in tumor permeability through NO production. In the BN472 tumor model, early reduction of permeability, as detected by K(trans) quantification using the dynamic contrast-enhanced magnetic resonance imaging contrasting agent P792 (Vistarem), was found to be a predictive marker for late-stage antitumor activity by NVP-BEZ235.
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PMID:Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. 1870 83

The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1alpha-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.
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PMID:mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work? 1879 63

How cyclic AMP (cAMP) could positively or negatively regulate G1 phase progression in different cell types or in cancer cells versus normal differentiated counterparts has remained an intriguing question for decades. At variance with the cAMP-dependent mitogenesis of normal thyroid epithelial cells, we show here that cAMP and cAMP-dependent protein kinase activation inhibit S-phase entry in four thyroid carcinoma cell lines that harbor a permanent activation of the Raf/ERK pathway by different oncogenes. Only in Ret/PTC1-positive TPC-1 cells did cAMP markedly inhibit the Raf/ERK cascade, leading to mTOR pathway inhibition, repression of cyclin D1 and p21 and p27 accumulation. p27 knockdown did not prevent the DNA synthesis inhibition. In the other cells, cAMP little affected these signaling cascades and levels of cyclins D or CDK inhibitors. However, cAMP differentially inhibited the pRb-kinase activity and T172-phosphorylation of CDK4 complexed to cyclin D1 or cyclin D3, whereas CDK-activating kinase activity remained unaffected. At variance with current conceptions, our studies in thyroid carcinoma cell lines and previously in normal thyrocytes identify the activating phosphorylation of CDK4 as a common target of opposite cell cycle regulations by cAMP, irrespective of its impact on classical mitogenic signaling cascades and expression of CDK4 regulatory partners.
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PMID:Cyclic AMP inhibits the proliferation of thyroid carcinoma cell lines through regulation of CDK4 phosphorylation. 1879 15

Inactivation and silencing of PTEN have been observed in multiple cancers, including follicular thyroid carcinoma. PTEN (phosphatase and tensin homologue deleted from chromosome 10) functions as a tumour suppressor by opposing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Despite correlative data, how deregulated PTEN signalling leads to thyroid carcinogenesis is not known. Mice harbouring a dominant-negative mutant thyroid hormone receptor beta (TRbeta(PV/PV) mice) spontaneously develop follicular thyroid carcinoma and distant metastases similar to human cancer. To elucidate the role of PTEN in thyroid carcinogenesis, we generated TRbeta(PV/PV) mice haploinsufficient for Pten (TRbeta(PV/PV)Pten(+/-) mouse). PTEN deficiency accelerated the progression of thyroid tumour and increased the occurrence of metastasis spread to the lung in TRbeta(PV/PV)Pten(+/-) mice, thereby significantly reducing their survival as compared with TRbeta(PV/PV)Pten(+/+) mice. AKT activation was further increased by two-fold in TRbeta(PV/PV)Pten(+/-) mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)-p70S6K signalling and decreased activity of the forkhead family member FOXO3a. Consistently, cyclin D1 expression was increased. Apoptosis was decreased as indicated by increased expression of nuclear factor-kappaB (NF-kappaB) and decreased caspase-3 activity in the thyroids of TRbeta(PV/PV)Pten(+/-) mice. Our results indicate that PTEN deficiency resulted in increased cell proliferation and survival in the thyroids of TRbeta(PV/PV)Pten(+/-) mice. Altogether, our study provides direct evidence to indicate that in vivo, PTEN is a critical regulator in the follicular thyroid cancer progression and invasiveness.
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PMID:PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer. 1899 18

Human papilloma virus (HPV) infection of the uterine cervix is linked to the pathogenesis of cervical cancer. Preclinical in vitro and in vivo studies using HPV-containing human cervical carcinoma cell lines have shown that the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, erlotinib, can induce growth delay of xenografts. Activation of Akt and mTOR are also observed in cervical squamous cell carcinoma and, the expression of phosphorylated mTOR was reported to serve as a marker to predict response to chemotherapy and survival of cervical cancer patients. Therefore, we investigated: a) the expression level of EGFR in cervical squamous cell carcinoma (SCC) and high-grade squamous intraepithelial lesions (HSIL) versus non-neoplastic cervical squamous epithelium; b) the state of activation of the mTOR pathway in these same tissues; and c) any impact of these signal transduction molecules on cell cycle. Formalin-fixed paraffin-embedded tissue microarray blocks containing 20 samples each of normal cervix, HSIL and invasive SCC, derived from a total of 60 cases of cervical biopsies and cervical conizations were examined. Immunohistochemistry was utilized to detect the following antigens: EGFR; mTOR pathway markers, phosphorylated (p)-mTOR (Ser2448) and p-p70S6K (Thr389); and cell cycle associated proteins, Ki-67 and S phase kinase-associated protein (Skp)2. Protein compartmentalization and expression were quantified in regard to proportion (0-100%) and intensity (0-3+). Mitotic index (MI) was also assessed. An expression index (EI) for pmTOR, p-p70S6K and EGFR, respectively was calculated by taking the product of intensity score and proportion of positively staining cells. We found that plasmalemmal EGFR expression was limited to the basal/parabasal cells (2-3+, EI = 67) in normal cervical epithelium (NL), but was diffusely positive in all HSIL (EI = 237) and SCC (EI 226). The pattern of cytoplasmic p-mTOR and nuclear p-p70S6K expression was similar to that of EGFR; all showed a significantly increased EI in HSIL/SCC versus NL (p<0.02). Nuclear translocation of p-mTOR was observed in all SCC lesions (EI = 202) and was significantly increased versus both HSIL (EI = 89) and NL (EI = 54) with p<0.015 and p<0.0001, respectively. Concomitant increases in MI and proportion of nuclear Ki-67 and Skp2 expression were noted in HSIL and SCC. In conclusion, morphoproteomic analysis reveals constitutive activation and overexpression of the mTOR pathway in HSIL and SCC as evidenced by: increased nuclear translocation of pmTOR and p-p70S6K, phosphorylated at putative sites of activation, Ser2448 and Thr389, respectively; correlative overexpression of the upstream signal transducer, EGFR, and increases in cell cycle correlates, Skp2 and mitotic indices. These results suggest that the mTOR pathway plays a key role in cervical carcinogenesis and targeted therapies may be developed for SCC as well as its precursor lesion, HSIL.
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PMID:Morphoproteomic evidence of constitutively activated and overexpressed mTOR pathway in cervical squamous carcinoma and high grade squamous intraepithelial lesions. 1907 19


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