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)

Activated mTOR was implicated to play a role in the carcinogenesis of nasopharyngeal carcinoma (NPC). However, the mechanism of activated mTOR/Complex1(mTORC1) signaling pathway in NPC development has not been well established. In this study, we correlated the expression of mTORC1 signal molecules and Cyclin D1 in NPC. We also investigated the effect of blocking mTORC1 signal with rapamycin and mTOR siRNA on Cyclin D1 expression in CNE-2 cells, as well as cell apoptosis and viability. We found a positive association of mTORC1 signal molecules and Cyclin D1 in NPC. Also, we found blockage mTORC1 inhibited Cyclin D1 expression in CNE-2 cells and enhanced cell apoptosis. Our results suggested that mTORC1 signal pathway might be a potential target for NPC therapy.
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PMID:Overproduction of cyclin D1 is dependent on activated mTORC1 signal in nasopharyngeal carcinoma: implication for therapy. 1920 29

In the field of energetics and cancer, little attention has been given to whether energy balance directed interventions designed to regulate body weight by increasing energy expenditure versus reducing energy intake have an equivalent effect on the development of breast cancer. The objective of this experiment was to determine the effects on mammary carcinogenesis of physical activity (PA), achieved via running on an activity wheel, or restricted energy intake (RE). Food intake of PA and RE rats was controlled so that both groups had the same net energy balance determined by growth rate, which was 92% of the sedentary control group (SC). A total of 135 female Sprague-Dawley rats were injected with 1-methyl-1-nitrosourea (50 mg/kg) and 7 days thereafter were randomized to either SC, PA, or RE. Mammary cancer incidence was 97.8%, 88.9%, and 84.4% and cancer multiplicity was 3.66, 3.11, and 2.64 cancers/rat in SC, RE, and PA, respectively (SC versus PA, P = 0.02 for incidence and P = 0.03 for multiplicity). Analyses of mammary carcinomas revealed that cell proliferation-associated proteins were reduced and caspase-3 activity and proapoptotic proteins were elevated by PA or RE relative to SC (P < 0.05). It was observed that these effects may be mediated, in part, by activation of AMP-activated protein kinase and down-regulation of protein kinase B and the mammalian target of rapamycin.
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PMID:Effects of physical activity and restricted energy intake on chemically induced mammary carcinogenesis. 1933 20

The development of targeted molecules in renal carcinogenesis changed the therapeutic approaches of treatment for metastatic clear cell renal cell carcinoma. Four available drugs are currently available, i.e. bevacizumab, sunitinib, sorafenib and temsirolimus, but other molecules and combined therapy are under investigation. In this review we assess published reports of these targeted therapies and discuss the novel promising molecules targeting vascular endothelial growth factor and its receptors, the mammalian target of rapamycin and epithelial growth factor cascade.
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PMID:Targeted therapies in metastatic renal cancer in 2009. 1933 65

Throughout many countries, lung cancer will kill more people this year than malignancies related to breast, prostate, colon, liver, kidney and melanoma combined. Despite recent advances in understanding the molecular biology of lung carcinoma and the introduction of multiple new chemotherapeutic agents for its treatment, its dismal five-year survival rate (<15%) has not changed substantially. The lack of advancement in this area reflects the limited knowledge available concerning the factors that promote oncogenic transformation and proliferation of carcinoma cells in the lung. Malignant transformation plays a key role in tumor growth and invasion; however, other factors such as the surrounding stroma, local growth factors, vascularity, and systemic hormones are important contributors as well. We believe that the composition of the lung extracellular matrix is also important due to its ability to affect malignant cell behavior in vitro. The matrix glycoprotein fibronectin, for example, is highly expressed in chronic lung disorders where most lung carcinomas are identified. This document reviews information that implicates fibronectin in the stimulation of lung carcinoma cell growth. Data available to date indicate that by binding to specific integrin receptors expressed on the surface of tumor cells, fibronectin stimulates intracellular signals implicated in the pathobiology of lung carcinogenesis and lung tumor chemoresistance including mitogen-activated protein kinases, GTPases, and the PI3-kinase/Akt/mTOR pathway. Thus, integrin-mediated signals triggered by fibronectin in tumor cells represent promising targets for the development of novel anti-cancer strategies.
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PMID:Stimulation of lung carcinoma cell growth by fibronectin-integrin signalling. 1939 78

Germline inactivation of the VHL tumor suppressor gene is associated with an increased risk of clear cell carcinoma of the kidney in the context of von Hippel-Lindau (VHL) disease. Somatic VHL mutations are also common in nonhereditary (sporadic) clear cell carcinomas. The VHL protein (pVHL) has multiple functions that might be linked to tumor suppression, including targeting the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. HIF, especially HIF2alpha, appears to play a causal role in clear cell renal carcinogenesis based on genotype-phenotype correlations in VHL disease, laboratory experiments with human VHL-/- renal carcinoma cell lines, and genetically engineered mouse models. Deregulation of HIF almost certainly accounts for the high levels of vascular endothelial growth factor (VEGF) observed in kidney cancer and relates to their sensitivity to VEGF inhibitors. In addition, the beneficial effects of mammalian target of rapamycin (mTOR) inhibitors are likely due to, at least partly, their ability to down-regulate HIF. pVHL, in a HIF-independent manner, also regulates a specialized structure called the primary cilium and regulates apoptosis via factors such as NFkappaB. Loss of the primary cilium probably facilitates the development of preneoplastic renal cysts, whereas increased NFkappaB might contribute to the resistance of kidney cancers to conventional cytotoxic agents.
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PMID:Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein. 1940 56

Notable advances have been achieved in head and neck cancer and in lung cancer as regards oncogenesis knowledge and treatment optimization. Multimodal management including molecular targeted therapies have provided a clear benefit in some circumstances. This review provides information on these two primary sites. Some issues are specific (non-tobacco-related carcinogenesis, antiangogenic agents) while some others are shared by both primary sites (oncogenesis, EGFR pathway targeting). Molecular targeted therapies have shifted some treatment algorithms in head and neck cancer (monoclonal antibodies targeting EGFR and radiotherapy in advanced diseases) and in lung cancer as well (1st line anti VEGFR antibodies, EGFR pathway tyrosin-kinase inhibitors as 2nd line treatment for metastatic diseases). Many new prospects are under evaluation (anti-EGFR antibodies, mTOR inhibitors, multi-targets agents, anti-IGFR1 antibodies). Molecular targeted therapies have also generated new protocols for disease evaluation, imaging and bio-clinical monitoring in order to better select patients and improve the outcome.
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PMID:[Information on head, neck and lung cancers]. 1943 69

AKT-mTOR pathway is considered as a key actor of the regulation of cell metabolism, interacting in network with multiple pathways implied in immune regulation and carcinogenesis. mTOR inhibitors were initially proposed as immunomodalting agents and are now developed as targeted therapy for non-hematologic solid tumours or lymphomas. This review proposes to synthesize knowledge on the AKT-mTOR pathway and the currently available data for head and neck or pulmonary tumours in order to present the value of these agents in this setting. Rational and preclinic results will then allow us to discuss potential future development of mTOR inhibitors.
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PMID:[Targeting of the AKT-mTOR pathway in head and neck and lung cancer]. 1943 74

Resveratrol (3,4',5-trans-trihydroxystilbene) is a phytoalexin with emerging lines of evidence supporting its beneficial effects on cardiovascular systems and inhibition of carcinogenesis. It has also been reported that certain methylated resveratrol derivatives are more effective than resveratrol in the prevention/treatment of cancer. However, little is known about the impact of resveratrol and its derivatives on the development of Parkinson's disease. In this study, we compared the neuroprotective effects of resveratrol with four methylated (fully or partially) resveratrol derivatives against parkinsonian mimetic 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. Release of lactate dehydrogenase and activity of caspase-3 triggered by 6-OHDA were significantly reduced by resveratrol and one of the methylated derivatives, pinostilbene (3,4'-dihydroxy-5-methoxystilbene), in a dose-dependent manner. In addition, pinostilbene exerted a potent neuroprotective effect with a wider effective concentration range than resveratrol. By using high-performance liquid chromatography, we found that uptake of pinostilbene into SH-SY5Y cells was significantly higher than that of resveratrol. Enhanced bioavailability may thus be a major factor contributing to the neuroprotective activity of pinostilbene. Moreover, Western blot analysis demonstrated that pinostilbene markedly attenuated the phosphorylation of JNK and c-Jun triggered by 6-OHDA. Besides, mammalian target of rapamycin kinase may be an intracellular target accounting for the neuroprotective effects of pinostilbene. Our findings demonstrate the potential of methylated stilbenes in neuroprotection and provide important information for further research in this field.
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PMID:Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells. 1944

Phosphorylated (pi-) protein kinase B (AKT) is commonly expressed in nasopharyngeal carcinoma (NPC) cell lines and tissues, suggesting the involvement of AKT-mammalian target of rapamycin (mTOR) signaling in NPC carcinogenesis. This study evaluated the activity of an mTOR inhibitor, RAD001 (Everolimus, Novartis Pharma AG, Switzerland), in 5 NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1), 2 cisplatin-resistant NPC cell lines and their respective parental cell lines (HK1-LMP1, HONE-1-EBV). RAD001 inhibited cell growth in a dose-dependent manner at nanomolar concentrations in all cell lines. HONE-1 was most sensitive to RAD001 (IC(50) = 0.63 nM, 60% maximal inhibition), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant. No consistent relationship between sensitivity to RAD001 and basal expression of pi-mTOR and pi-p70S6 Kinase-1 (p70S6K) was found. Exposure to RAD001 at picomolar concentrations for 48 h resulted in reduction of pi-mTOR and pi-p70S6K1 expression, but increase in pi-AKT (Ser473) expression in HONE-1 and CNE-1 cell lines. RAD001 significantly induced apoptosis in HONE-1 cells, but has no effect on cell cycle progression. RAD001 exerted an additive to synergistic effect on cisplatin-induced growth inhibition in CNE-1 and HONE-1 cells, and could inhibit the growth of both cisplatin-resistant and cisplatin-sensitive NPC cell lines. In summary, combination of RAD001 and cisplatin maybe a useful therapeutic strategy in NPC. AKT upregulation following RAD001 treatment suggests the presence of a feedback loop on AKT signaling in NPC which warrants further investigation.
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PMID:The activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell lines. 1947 57

Evidence is strong that a reduction in risk for breast cancer is associated with moderate to vigorous physical activity (PA); however, there is limited understanding of the role of type, intensity, duration, and frequency of PA and their mechanisms in accounting for this health benefit. The objective of this review is to stimulate investigations of candidate mechanisms that may account for the effects of the intensity and duration of aerobic PA on breast cancer risk and tumor burden. Three hypotheses are considered: 1) the mTOR network hypothesis: PA inhibits carcinogenesis by suppressing the activation of the mTOR signaling network in mammary carcinomas; 2) the hormesis hypothesis: the carcinogenic response to PA is nonlinear and accounted for by a physiological cellular stress response; and 3) the metabolic reprogramming hypothesis: PA limits the amount of glucose and glutamine available to mammary carcinomas thereby inducing apoptosis because tumor-associated metabolic programming is reversed. To link these hypotheses to systemic effects of PA, it is recommended that consideration be given to determining: 1) what contracting muscle releases into circulation or removes from circulation that would directly modulate the carcinogenic process in epithelial cells; 2) whether the effects of muscle contraction on epithelial cell carcinogenesis are exerted in an endocrine, paracrine, autocrine, or intracrine manner; and 3) if the effects of muscle contraction on malignant cells differ from effects on normal or premalignant cells that do not manifest the hallmarks of malignancy.
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PMID:Candidate mechanisms accounting for effects of physical activity on breast carcinogenesis. 1958 23


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