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)

In search of new strategies for the therapy of advanced tumors stroma-targeted approaches have been discussed recently, especially antiangiogenic therapies. It has turned out that some biomodulating drugs exhibit also effects against tumors beyond their original non-oncologic indication. Among these drugs are for example thalidomide,COX-2 inhibitors, PPARgamma agonists (thiazolidindiones) and mTOR antagonists (rapamycin). The antitumor efficacy of these therapeutics is fundamentally based on indirect effects on the stroma of the tumors. Combination therapies of these therapeutics seem to be superior to the use of single agents. These new biomodulating therapy approaches represent an interesting option for the palliative treatment of advanced tumors, especially as a supplement or extension of established chemo- and immunotherapeutic therapies, since they can be performed in an outpatient setting, the observed side effects are usually mild, and the therapies are therefore well accepted by the patients.
J Dtsch Dermatol Ges 2006 Mar
PMID:[Stroma-targeted palliative tumor therapy with biomodulators]. 1662 22

Keloid, a chronic fibro-proliferative disease, exhibits distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells (MCs), and a milieu of enriched cytokines. Previous studies have demonstrated that co-culture with MCs stimulate type I collagen synthesis in fibroblasts, but the signaling mechanisms remain largely unknown. In this study, we investigated the signaling pathways involved in MC-stimulated type I collagen synthesis and the effects of green tea extract (GTE) and its major catechin, (-)-epigallocatechin-3-gallate (EGCG), on collagen homeostasis in keloid fibroblasts. Our results showed that MCs significantly stimulated type I collagen expression in keloid fibroblasts, and the upregulation of type I collagen was significantly attenuated by blockade of phosphatidylinositol-3-kinase (PI-3K), mammalian target of rapamycin (mTOR), and p38 MAPK signaling pathways, but not by blockade of ERK1/2 pathway. Furthermore, GTE and EGCG dramatically inhibited type I collagen production possibly by interfering with the PI-3K/Akt/mTOR signaling pathway. Our findings suggest that interaction between MCs and keloid fibroblasts may contribute to excessive collagen accumulation in keloids and imply a therapeutic potential of green tea for the intervention and prevention of keloids and other fibrotic diseases.
J Invest Dermatol 2006 Dec
PMID:Green tea extract and (-)-epigallocatechin-3-gallate inhibit mast cell-stimulated type I collagen expression in keloid fibroblasts via blocking PI-3K/AkT signaling pathways. 1684 Oct 34

The missed mark or hamartia underlying each hamartoma syndrome is a mutation in a tumor suppressor gene. This sets the stage for the development of frequent and early tumors in multiple organs. Loss of function of the tumor suppressor in neoplastic cells leads to dysregulation of signaling pathways and tumor growth. The convergence of these signaling pathways to the mTOR pathway suggests that rapamycin or rapamycin-like drugs have potential for treatment, perhaps in combination with drugs targeting other signaling pathways. Haploinsufficient cells also play significant roles in tumor formation. Disrupting interactions between neoplastic cells and surrounding haploinsufficient cells using antiangiogenesis therapies represent an additional approach for treatment. It is hoped that the debilitating effects of these syndromes soon will be alleviated or even reversed though targeted therapies.
Adv Dermatol 2006
PMID:Hitting the mark in hamartoma syndromes. 1724 2

Keloid is a dermal fibroproliferative disorder characterized by excessive deposition of extracellular matrix (ECM) components such as collagen, glycoproteins and fibronectin. The mammalian target of rapamycin (mTOR) is a serine/theronine kinase which plays an important role in the regulation of metabolic processes and translation rates. Published reports have shown mTOR as regulator of collagen expression and its inhibition induces a decrease in ECM deposition. Our aim was to investigate the role of mTOR in keloid pathogenesis and investigate the effect of rapamycin on proliferating cell nuclear antigen (PCNA), cyclin D1, collagen, fibronectin and alpha-smooth muscle actin (alpha-SMA) expression in normal fibroblasts (NF) and keloid fibroblasts (KF). Tissue extracts obtained from keloid scar demonstrated elevated expression of mTOR, p70KDa S6 kinase (p70S6K) and their activated forms, suggesting an activated state in keloid scars. Serum stimulation highlighted the heightened responsiveness of KF to mitogens and the importance of mTOR and p70S6K during early phase of wound healing. Application of rapamycin to monoculture NF and KF, dose- and time-dependently downregulates the expression of cytoplasmic PCNA, cyclin D1, fibronectin, collagen and alpha-SMA, demonstrating the anti-proliferative effect and therapeutic potential of rapamycin in the treatment of keloid scars. The inhibitory effect of rapamycin was found to be reversible following recovery in the expression of proteins following the removal of rapamycin from the culture media. These results demonstrate the important role of mTOR in the regulation of cell cycle and the expression of ECM proteins: fibronectin, collagen and alpha-SMA.
Exp Dermatol 2007 May
PMID:mTOR as a potential therapeutic target for treatment of keloids and excessive scars. 1743 82

Discovered in fungi in the remote Easter Island, sirolimus (rapamycin) shows potential beyond its obvious antiproliferative and immunosuppressant activity. Studies have demonstrated that sirolimus acts as a vascular endothelial growth factor inhibitor, providing prospective therapeutic benefits and possible prevention of tuberous sclerosis and Kaposi's sarcoma. Its ability to decrease keratinocyte proliferation may help patients with psoriasis. In those with tuberous sclerosis complex, it may prevent the development of hamartomas and reduce or eliminate them once grown by blocking the mammalian target of rapamycin, a critical regulatory kinase. A great advantage for this drug is in the decreased risk of malignancies, including Kaposi's sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors. This review will focus on the pharmacology and potential uses of sirolimus.
J Am Acad Dermatol 2007 Dec
PMID:Sirolimus (rapamycin): from the soil of Easter Island to a bright future. 1758 72

The objective of this study was to determine whether activation of the kinase mammalian target of rapamycin (mTOR) is associated with human melanoma. We found moderate or strong hyperphosphorylation of ribosomal protein S6 in 78/107 melanomas (73%). In contrast, only 3/67 benign nevi (4%) were moderately positive, and none were strongly positive. These data indicate that mTOR activation is very strongly associated with malignant, compared to benign, melanocytic lesions. Next, we tested six melanoma-derived cell lines for evidence of mTOR dysregulation. Five of the six lines showed persistent phosphorylation of S6 after 18 hours of serum deprivation, and four had S6 phosphorylation after 30 minutes of amino-acid withdrawal, indicating inappropriate mTOR activation. The proliferation of three melanoma-derived lines was blocked by the mTOR inhibitor rapamycin, indicating that mTOR activation is a growth-promoting factor in melanoma-derived cells. mTOR is directly activated by the small guanosine triphosphatase Ras homolog enriched in brain (Rheb), in a farnesylation-dependent manner. Therefore, to investigate the mechanism of mTOR activation, we used the farnesyl transferase inhibitor FTI-277, which partially blocked the growth of three of the six melanoma cell lines. Together, these data implicate activation of mTOR in the pathogenesis of melanoma, and suggest that Rheb and mTOR may be targets for melanoma therapy.
J Invest Dermatol 2008 Apr
PMID:mTOR is activated in the majority of malignant melanomas. 1791 50

Tumor necrosis factor-alpha (TNF-alpha) is induced by UVB radiation and has been implicated in the early stages of skin carcinogenesis. Here, we show that in normal keratinocytes and the transformed keratinocyte cell lines, HaCaT and A431, TNF-alpha stimulates protein kinase B/Akt, which results in activation of the survival complex mTORC1 (mammalian target of rapamycin complex 1) and inhibition of the proapoptotic proteins Bad and FoxO3a. In UVB-irradiated HaCaT cells (10-20 mJ cm(-2)), TNF-alpha increased the proportion of cycling cells and enhanced the rate of apoptosis. A significantly higher proportion of UVB-treated HaCaT cells containing unrepaired cyclobutane pyrimidine dimers (CPDs) escaped the G2/M cell cycle checkpoint in the presence of TNF-alpha (9.5+/-3.3 vs 4.8+/-2.2%). After treatment with the PI3K inhibitor LY294002, only 1.2+/-0.7% of CPD-containing HaCaT cells were actively cycling. TNF-alpha enhanced apoptosis less potently and did not increase the level of CPD or stimulate cell cycle progression in normal keratinocytes. Our data suggest that TNF-alpha overrides the G2/M checkpoint in premalignant skin cells and allows for some cells containing unrepaired CPD to enter the cell cycle. The effect of TNF-alpha seems to be dependent on Akt activation and may constitute a relevant mechanism enhancing mutagenesis and tumor development.
J Invest Dermatol 2008 Aug
PMID:TNF-alpha impairs the S-G2/M cell cycle checkpoint and cyclobutane pyrimidine dimer repair in premalignant skin cells: role of the PI3K-Akt pathway. 1827 51

The RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways are activated through multiple mechanisms and appear to play a major role in melanoma progression. Herein, we examined whether targeting the RAS-RAF-MEK-ERK pathway with the RAF inhibitor sorafenib and/or the PI3K-AKT-mTOR pathway with the mTOR inhibitor rapamycin has therapeutic effects against melanoma. A combination of sorafenib (4 microM) with rapamycin (10 nM) potentiated growth inhibition in all six metastatic melanoma cell lines tested. The absolute enhancement of growth inhibition rates ranged from 13.0-27.8% in different cell lines (P<0.05, combination treatment vs monotreatment). Similar results were obtained with combinations of the MEK inhibitors U0126 (30 microM) or PD98059 (50 microM) with rapamycin (10 nM). The combined treatment of melanoma cells with sorafenib and rapamycin led to an approximately twofold increase of cell death compared with sorafenib monotreatment (P<0.05) as assessed by propidium iodide staining and cell death detection ELISA. Moreover, sorafenib in combination with rapamycin completely suppressed invasive melanoma growth in organotypic culture mimicking the physiological context. These effects were associated with complete downregulation of the antiapoptotic proteins Bcl-2 and Mcl-1. Sorafenib combined with rapamycin appears to be a promising strategy for the effective treatment of melanoma and merits clinical investigation.
J Invest Dermatol 2008 Aug
PMID:Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. 1832 81

The multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) is known to play an important role in inflammatory and immunological responses in human skin. Although it has been documented that reactive oxygen species (ROS) are involved in TNF-alpha-induced signaling pathways associated with certain inflammatory diseases, their role in TNF-alpha signaling cascades has not been examined in primary human keratinocytes used as a model of inflammatory skin disease and psoriasis. Employing a series of in vitro and in cellulo approaches, we have demonstrated that in primary human keratinocytes (i) TNF-alpha rapidly induces ROS generation, IkappaB degradation, NF-kappaB p65 nuclear translocation, and ultimately production of inflammatory cytokines; (ii) TNF-alpha-induced cytokine production is mediated both by the mammalian target of rapamycin signaling pathway via NF-kappaB activation and by ROS; (iii) TNF-alpha-dependent NF-kappaB activation (that is, IkappaB degradation and NF-kappaB p65 nuclear translocation) is not mediated by ROS; and (iv) a cell-penetrating derivative of the antioxidant enzyme, catalase, as well as taurine and N-acetyl-cysteine attenuate the TNF-alpha-induced production of cytokines. These latter results suggest that catalase and perhaps other antioxidants should be considered as part of a more specific and effective therapy for the treatment of inflammatory skin diseases, including psoriasis.
J Invest Dermatol 2008 Nov
PMID:Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. 1846 78

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an incidence of approximately one in 6000. It arises from a genetic abnormality involving either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. The protein product of TSC1 is hamartin and that of TSC2 is tuberin. In cells, hamartin and tuberin form a complex which inhibits the mammalian target of rapamycin (mTOR), a central controller of cell growth and proliferation. Angiofibroma affects 70-80% of patients with TSC, typically on the face. We report a patient with TSC with recurrent life-threatening haemorrhage from both kidneys due to extensive angiomyolipoma formation leading to bilateral nephrectomy and renal transplantation. Immunosuppressive treatment with rapamycin, a specific mTOR inhibitor, initiated because of renal transplantation, reduced facial angiofibroma dramatically.
Br J Dermatol 2008 Aug
PMID:The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. 1854 4


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