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

Mammalian target of rapamycin (mTOR) has been shown to play an important function in cell proliferation, metabolism and tumorigenesis, and proteins that regulate signaling through mTOR are frequently altered in human cancers. In this study we investigated the phosphorylation status of key proteins in the PI3K/AKT/mTOR pathway and the effects of the mTOR inhibitors rapamycin and CCI-779 on neuroblastoma tumorigenesis. Significant expression of activated AKT and mTOR were detected in all primary neuroblastoma tissue samples investigated, but not in non-malignant adrenal medullas. mTOR inhibitors showed antiproliferative effects on neuroblastoma cells in vitro. Neuroblastoma cell lines expressing high levels of MYCN were significantly more sensitive to mTOR inhibitors compared to cell lines expressing low MYCN levels. Established neuroblastoma tumors treated with mTOR inhibitors in vivo showed increased apoptosis, decreased proliferation and inhibition of angiogenesis. Importantly, mTOR inhibitors induced downregulation of vascular endothelial growth factor A (VEGF-A) secretion, cyclin D1 and MYCN protein expression in vitro and in vivo. Our data suggest that mTOR inhibitors have therapeutic efficacy on aggressive MYCN amplified neuroblastomas.
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PMID:Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. 1802 38

High-grade primary brain tumors remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of these malignant tumors and identify oncogenic pathways that might be amenable to small-molecule and antibody 'targeted' therapy. Growth factor signaling pathways are often upregulated in these tumors and contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the downstream Ras signaling pathway. Other internal signal transduction pathways that may become dysregulated during transformation include Raf, MEK, PI3K, Akt (protein kinase B), and mTOR (mammalian target of rapamycin). In addition, overactivity of VEGF and other effectors leads to neoplastic angiogenesis. 'Targeted' therapy against the growth factor signaling and Ras pathways include tyrosine kinase inhibitors (eg, imatinib and erlotinib) and farnesyltransferase inhibitors (eg, tipifarnib). Molecular therapeutic small molecules specific to Raf, PI3K, and mTOR include sorafenib, LY-294002, and temsirolimus, respectively. 'Targeted' anti-angiogenesis approaches include mAbs to VEGF (eg, bevacizumab) and VEGF receptor tyrosine kinase inhibitors (eg, vatalanib and sunitinib). Further development of 'targeted' therapies designed to modulate the activity of these pathways, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality-of-life for patients with malignant brain tumors.
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PMID:Small-molecule and antibody approaches to molecular chemotherapy of primary brain tumors. 1805 72

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with an annual occurrence of one million new cases. At present there is no effective treatment for HCC individuals that not amenable to curative therapies. Recent studies show the PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Rapamycin (a specific Mtor inhibitor) could lead to G(1) arrest of many malignant cell lines, and currently analogs of rapamycin are being investigated as a cancer chemotherapeutic adjuvant. This study investigated rapamycin and chemotherapeutic agent 5-fluorouracil (5-Fu) in combination treatment induced apoptosis and cell senescence in hepatocarcinoma cell line SMMC-7721 cells. Treating SMMC-7721 cells with rapamycin plus 5-Fu led to not only apoptosis but also cell senescence, and the senescent cells exhibited significantly less clonogenic potential than 5-Fu individually treated cells. Further study showed rapamycin plus 5-Fu-induced senescence-like growth arrest was accompanied by down-regulation of AP-1 and NF kappa B transcription activity. These results suggest that inhibitors of mTOR may have anticancer potential when used together with some other chemotherapeutic agents, and that down-regulation of AP-1 and NF kappa B transcription activity might take part in a senescence-like growth arrest program induced by rapamycin plus 5-Fu.
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PMID:Synergistic effect of mTOR inhibitor rapamycin and fluorouracil in inducing apoptosis and cell senescence in hepatocarcinoma cells. 1834 84

Survivin plays important roles in maintaining cell proliferation and survival and promoting tumorigenesis. The present study was conducted to determine the stage of lung carcinogenesis at which survivin expression is induced and to investigate how survivin affects the chemopreventive action of deguelin. In in vitro studies, we observed higher levels of survivin expression in a subset of premalignant and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines than in normal HBE cells, and in in vivo studies, a higher level of survivin expression in specimen of human lung dysplasia than in normal lung specimens. Treatment with deguelin inhibited de novo synthesis of survivin protein and induced apoptosis, resulting in suppression of transformation phenotypes, in the premalignant and malignant HBE and NSCLC cell lines. Deguelin inhibited survivin expression in tuberous sclerosis complex 2 (TSC2) wild-type mouse embryonic fibroblasts (MEF) but not in TSC2-knockout MEFs in which mammalian target of rapamycin (mTOR) is constitutively active. Deguelin induced activation of AMP-activated protein kinase (AMPK) and inactivation of Akt. Overexpression of constitutively active Akt abolished deguelin-induced modulation of AMPK activity and survivin expression. Conversely, inactivation of AMPK by compound C or AMPKalpha1/2 small interfering RNA restored Akt and mTOR activities and survivin expression in deguelin-treated HBE cells. These results suggest that survivin expression is induced as an early event in lung carcinogenesis, and deguelin acts as a chemopreventive agent by inducing a reciprocal regulation between AMPK and Akt, resulting in the inhibition of mTOR-mediated survivin.
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PMID:Implication of AMP-activated protein kinase and Akt-regulated survivin in lung cancer chemopreventive activities of deguelin. 1808 92

mTORC2 is a multimeric kinase composed of the mammalian target of rapamycin kinase (mTOR), mLST8, mSin1, and rictor. The complex is insensitive to acute rapamycin exposure and has shown functions in controlling cell growth and actin cytoskeletal assembly. mTORC2 has recently been shown to phosphorylate and activate Akt. Because approximately 70% of gliomas harbor high levels of activated Akt, we investigated whether mTORC2 activity was elevated in gliomas. In this study, we found that mTORC2 activity was elevated in glioma cell lines as well as in primary tumor cells as compared with normal brain tissue (P < 0.05). Moreover, we found that rictor protein and mRNA levels were also elevated and correlated with increased mTORC2 activity. Overexpression of rictor in cell lines led to increased mTORC2 assembly and activity. These lines exhibited increased anchorage-independent growth in soft agar, increased S-phase cell cycle distribution, increased motility, and elevated integrin beta(1) and beta(3) expression. In contrast, small interfering RNA-mediated knockdown of rictor inhibited these oncogenic activities. Protein kinase C alpha (PKC alpha) activity was shown to be elevated in rictor-overexpressing lines but reduced in rictor-knockdown clones, consistent with the known regulation of actin organization by mTORC2 via PKC alpha. Xenograft studies using these cell lines also supported a role for increased mTORC2 activity in tumorigenesis and enhanced tumor growth. In summary, these data suggest that mTORC2 is hyperactivated in gliomas and functions in promoting tumor cell proliferation and invasive potential due to increased complex formation as a result of the overexpression of rictor.
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PMID:mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. 1808 1

Inactivating mutations in NF1 underlie the prevalent familial cancer syndrome neurofibromatosis type 1 [1]. The NF1-encoded protein is a Ras GTPase-activating protein (RasGAP) [2]. Accordingly, Ras is aberrantly activated in NF1-deficient tumors; however, it is unknown which effector pathways critically function in tumor development. Here we provide in vivo evidence that TORC1/mTOR activity is essential for tumorigenesis. Specifically, we show that the mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model. However, in these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1 [3]. These results demonstrate that mTOR inhibitors may be an effective targeted therapy for this commonly untreatable malignancy. Moreover, they indicate that mTOR inhibitors do not suppress all tumor types via the same mechanism, suggesting that current biomarkers that rely on HIF-1alpha suppression may not be informative for all cancers. Finally, our results reveal important differences between the effects of mTOR inhibition on the microvasculature in genetically engineered versus xenograft models and indicate that the former may be required for effective preclinical screening with this class of inhibitors.
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PMID:TORC1 is essential for NF1-associated malignancies. 1816 2

The therapeutic goal of cancer treatment has been to trigger tumor-selective cell death. Although cell death can be achieved not only by apoptosis (type I programmed cell death) but also by necrosis, mitotic catastrophe, and autophagy, drugs inducing apoptosis remain the main chemotherapeutic agents in medical oncology. However, cancer cells in their relentless drive to survive, hijack cell processes, resulting in apoptosis resistance, which underlies not only tumorigenesis but also the inherent resistance of certain cancers to radiotherapy and chemotherapy. Unlike apoptosis, which is a caspase-dependent process characterized by nuclear condensation and fragmentation, autophagic cell death is a caspase-independent process characterized by the accumulation of autophagic vacuoles in the cytoplasm accompanied by extensive degradation of the Golgi apparatus, the polyribosomes, and the endoplasmic reticulum, which precedes the destruction of the nucleus. The most striking evidence for proautophagic chemotherapy to overcome apoptosis resistance in cancer cells comes from the use of temozolomide, a proautophagic cytotoxic drug, which has demonstrated real therapeutic benefits in glioblastoma patients and is in clinical trials for several types of apoptosis-resistant cancers. A number of potential common targets in autophagy and apoptosis resistance pathways, that is, mammalian target of rapamycin (mTOR), phosphatidylinositol 3' kinase (PI3K), and Akt have been identified. Thus, further success in certain devastating cancers might be achieved by the combination of proautophagic drugs such as temozolomide with mTOR, PI3K, or Akt inhibitors, or with endoplasmic reticulum stress inhibitors as adjuvant chemotherapies.
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PMID:Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. 1816 16

Cell proliferation requires nutrients, energy, and biosynthetic activity to duplicate all macromolecular components during each passage through the cell cycle. It is therefore not surprising that metabolic activities in proliferating cells are fundamentally different from those in nonproliferating cells. This review examines the idea that several core fluxes, including aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis, form a stereotyped platform supporting proliferation of diverse cell types. We also consider regulation of these fluxes by cellular mediators of signal transduction and gene expression, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR system, hypoxia-inducible factor 1 (HIF-1), and Myc, during physiologic cell proliferation and tumorigenesis.
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PMID:The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. 1817 21

The Akt pathway is one of the most common molecular alterations in various human malignancies. However, its involvement in nasopharyngeal carcinoma (NPC) tumorigenesis has not been well established. In this study, the status of Akt activation and expression of its upstream and downstream molecules was investigated in 64 NPC and 38 non-malignant nasopharyngeal tissues by immunohistochemistry. The hotspot mutations of PIK3CA, encoding the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), were also determined in 25 of these NPC tissues. No hotspot mutations were found in any of the samples tested. Akt was activated in 27 (42.2%) and 23 (35.9%) NPCs, as indicated by p-Akt (Thr308) and p-Akt (Ser473) immunoreactivity, respectively. PTEN loss did not correlate statistically with activated Akt. However, a positive correlation was observed between activated Akt and phospho-epidermal growth factor receptor (p-EGFR), suggesting that the EGFR signaling might be one of the upstream regulators of the Akt pathway. The phosphorylation of forkhead (FKHR) and Bcl-2 associated death domain (BAD), but not mammalian target of rapamycin and glycogen synthase kinase-3beta, was significantly correlated with Akt activation. This implies that Akt promotes cell proliferation (as estimated by Ki-67) and survival, at least, through the inactivation of FKHR and BAD in NPC. Our data revealed that the EGFR/PI3K/Akt signaling pathway is important in NPC pathogenesis and that PIK3CA hotspot mutations are rare in NPC.
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PMID:Overexpression of phospho-Akt correlates with phosphorylation of EGF receptor, FKHR and BAD in nasopharyngeal carcinoma. 1820 77

Ras is a key regulator of the MAP kinase-signaling cascade and may cause morphologic change of Ras-transformed cells. Signal transducer and activator of transcription 3 (Stat3) can be activated by cytokine stimulation. In this study, we unravel that Ha-ras(V12) overexpression can downregulate the expression of Stat3 protein at a posttranslational level in NIH3T3 cells. Furthermore, we demonstrate that Stat3 expression downregulated by Ha-ras(V12) overexpression is through proteosome degradation and not through a mTOR/p70S6K-related signaling pathway. The suppression of Stat3 accompanied by the morphologic change induced by Ha-ras(V12) was through mitogen extracellular kinase (MEK)/extracellular-regulated kinase (ERK) signaling pathway. Microtubule disruption is involved in Ha-ras(V12)-induced morphologic change, which could be reversed by overexpression of Stat3. Taken together, we are the first to demonstrate that Stat3 protein plays a critical role in Ha-ras(V12)-induced morphologic change. Oncogenic Ras-triggered morphologic change is through the activation of MEK/ERK to posttranslationally downregulate Stat3 expression. Our finding may shed light on developing novel therapeutic strategies against Ras-related tumorigenesis.
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PMID:Oncogenic Ras-induced morphologic change is through MEK/ERK signaling pathway to downregulate Stat3 at a posttranslational level in NIH3T3 cells. 1823 38


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