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)

Loss of the PTEN tumor suppressor is a common occurrence in human prostate cancer, particularly in advanced disease. In keeping with its role as a pivotal upstream regulator of the phosphatidylinositol 3-kinase signaling pathway, experimentally-induced deletion of Pten in the murine prostate invariably results in neoplasia. However, and unlike humans where prostate tumorigenesis likely evolves over decades, disease progression in the constitutively Pten deficient mouse prostate is relatively rapid, culminating in invasive cancer within several weeks post-puberty. Given that the prostate undergoes rapid androgen-dependent growth at puberty, and that Pten excisions during this time might be especially tumorigenic, we hypothesized that delaying prostate-specific Pten deletions until immediately after puberty might alter the pace of tumorigenesis. To this end we generated mice with a tamoxifen-inducible Cre recombinase transgene enabling temporal control over prostate-specific gene alterations. This line was then interbred with mice carrying floxed Pten alleles. Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions. These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16-20 wks post-tamoxifen exposure, to overtly malignant lesions by approximately 1 yr of age, characterized by high-grade PIN and microinvasive carcinoma. In contrast, when Pten excisions were triggered in the pre-pubertal (2 week-old) prostate, neoplasia evolved over a more abbreviated time-frame, with a spectrum of premalignant lesions, as well as overt PIN and microinvasive carcinoma by 10-12 wks post-tamoxifen exposure. These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.
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PMID:The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision. 1908 94

Malignant renal tumors constitute 3% of human cancers, although their frequency differs greatly in various areas. Since the fifties, the incidence of renal cancers has been increasing, but at the some time the prognosis has been improving. In particular, in the last years, several new treatment modalities have been introduced, relying on the understanding of renal cancer biology. The identified etiological factors include smoking, increased body mass, dietary factors and chronic renal disease. There are several renal tumor types differing in morphology, molecular genetics and biology. Inactivation of the VHL gene leads to formation of the most frequent form in adults, namely clear cell carcinoma. The VHL gene product, a component of an ubiquitin-ligase complex, regulates expression of several genes. Papillary carcinomas depend mainly on the HGF receptor gene (c-Met) activating mutations. At least two types of papillary carcinomas exist, which have different morphology and prognosis. The molecular biology of chromophobe carcinoma and oncocytoma is poorly understood. Differential diagnosis of these tumors is particularly difficult and may require extensive immunohistochemical and molecular studies. Collecting duct carcinoma and medullary carcinoma are extremely aggressive but rare tumors. Some renal tumors have been described or recognized only relatively recently; these newer entities include multilocular cystic clear cell carcinoma, spindle cell papillary mucinous carcinoma, tubulocystic carcinoma, renal epithelial and stromal tumor, epithelioid and oncocytic angiomyolipoma. Besides histological typing, the prognostic factors include tumor stage, grade and several immunohistochemical and molecular markers that are currently under elaboration. The improved prognosis in renal cancer depends on earlier detection, but also on refinement of therapeutic methods. Small tumors may currently be treated by partial nephrectomy or radiofrequency ablation and larger ones by a laparoscopic approach. All these methods seem to give satisfactory results with low morbidity and mortality rates. Renal carcinoma is notorious for its low sensitivity to chemotherapy and radiotherapy. For several years, immunological treatment with IL-2 and INF-alpha was the only adjuvant therapy method. However, recently several new drugs have been introduced; they act on tyrosine-kinase receptors, VEGF, c-Met or mTOR pathway. With this progress, perfect understanding of renal tumor biology and exact histological diagnosis have become of prime practical importance.
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PMID:Pathology of renal tumors in adults. Molecular biology, histopathological diagnosis and prognosis. 1909 56

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

The genes TSC1 and TSC2, encoding hamartin and tuberin, respectively, have been shown to be involved in the development of the autosomal dominantly inherited tumor syndrome tuberous sclerosis (TSC). However, inactivation of these genes has also been demonstrated to be associated with sporadic bladder cancer, ovarian and gall bladder carcinoma, non-small-cell carcinoma of the lung, breast cancer, pancreatic cancer, astrocytoma, xanthoastrocytoma, ependymomas, oral squamous cell carcinoma and endometrial cancer. The hamartin/tuberin protein complex plays a central role in the regulation of the mammalian target of rapamycin (mTOR) signalling network. A wide variety of components of the mTOR cascade have been demonstrated to be involved in many different human cancers. Mutations in several mTOR pathway component genes are known to cause specific monogenic human genetic diseases and this signalling cascade has been shown to be of relevance for Alzheimer's disease, type 2 diabetes, obesity and hypertrophy. Consequently, e.g. clinical trials for the treatment with rapamycin, a negative regulator of mTOR, of hamartomas in TSC have already been initiated. Now the first evidence is provided for an involvement of the TSC genes in acute leukemia.
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PMID:New insights into the role of the tuberous sclerosis genes in leukemia. 1925 Jun 71

Over-expression of eIF4E indicates a poor prognosis in different tumors. In the present study, we investigated the frequency of eIF4E, 4E-BP1 and phosphorylated 4E-BP1 expression in PDAC cell lines, gastric carcinoma (GC) cell lines and human embryonic pancreatic cells, as well as gene therapy using translation repressor gene 4E-BP1 in combination with the mTOR inhibitor rapamycin. We also assessed the significance of eIF4E expression in 80 PDAC cases. Combination therapy of adenovirus vector-delivered 4E-BP1 gene and rapamycin was administered to determine their growth inhibition effect in vitro and in vivo in mice. Our study revealed that all PDAC cell lines, GC cell lines and human embryonic pancreas-derived cells expressed the 25-kDa eIF4E protein (MIAPaca-2 cells also expressed the 13-kDa protein 4E-BP1). The 80 PDAC specimens showed a heterogeneous pattern of eIF4E staining. No significant correlation between eIF4E expression and TNM classification was found. Adenovirus vectors Ad-4E-BP1 and Ad-GFP efficiently showed transgenic expression with hyperphosphorylation of 4E-BP1; however, insignificant growth inhibition of the PDAC and GC cell lines was observed. Combination therapy with rapamycin significantly inhibited proliferation and tumor growth in vitro as well as in vivo. Therefore, combination of Ad 4E-BP1 and rapamycin may be a more effective adjuvant therapy.
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PMID:Adenovirus-mediated eukaryotic initiation factor 4E binding protein-1 in combination with rapamycin inhibits tumor growth of pancreatic ductal adenocarcinoma in vivo. 1936 Mar 36

The tumor suppressor phosphatase and tensin homolog (PTEN) is frequently involved in human prostate carcinoma. PTEN is therefore an attractive target for the development of preclinical animal models. Prostate intraepithelial neoplasia lesions develop in mice with Pten heterozygosity, but disease progression has been reported only in combination with either other tumor suppressor gene alterations or the conditional inactivation of both Pten alleles in prostate epithelial cells. We report that on a C57BL/6 background, in contrast to previous studies on mixed 129 genetic backgrounds, Pten locus heterozygosity is fully penetrant for the development of prostate adenocarcinoma. Grossly observable tumors were detected at 6 months of age, and, by 10 to 12 months, 100% of examined mice developed adenocarcinoma of the anterior prostate. Furthermore, double heterozygotes carrying both Pten and Tsc2-null alleles showed no increase relative to Pten(+/-) heterozygotes in either lesion development or progression. Lesions in both Pten(+/-); Tsc2(+/-), and Pten(+/-) mice exhibited loss of PTEN expression and activation of PI3K signaling. PI3K activation occurred early in prostate intraepithelial neoplasia lesion formation in these animals, consistent with loss of PTEN function, and contributed to the etiology of tumors that developed in Pten(+/-) mice. Furthermore, prostate lesion growth in Pten(+/-) mice was dependent on mTOR, as evidenced by a reduction in both phospho-S6 levels and proliferative index after rapamycin treatment.
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PMID:PTEN deficiency is fully penetrant for prostate adenocarcinoma in C57BL/6 mice via mTOR-dependent growth. 1939 52

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

Head and neck squamous cell carcinomas (HNSCC), the majority of which occur in the oral cavity, remain a significant cause of morbidity and mortality worldwide. A major limitation in HNSCC research has been the paucity of animal models to test the validity of current genetic paradigms of tumorigenesis and to explore the effectiveness of new treatment modalities and chemopreventive strategies. Here, we have developed an inducible oral-specific animal tumor model system, which consists in the expression of a tamoxifen-inducible Cre recombinase (CreER(tam)) under the control of the cytokeratin 14 (K14) promoter (K14-CreER(tam)) and mice in which the endogenous K-ras locus is targeted (LSL-K-ras(G12D)), thereby causing the expression of endogenous levels of oncogenic K-ras(G12D) following removal of a stop element. Surprisingly, whereas K14-CreER(tam) can also target the skin, K14-CreER(tam)/LSL-K-ras(G12D) mice developed papillomas exclusively in the oral mucosa within 1 month after tamoxifen treatment. These lesions were highly proliferative but never progressed to carcinoma. However, when crossed with p53 conditional knockout (p53(flox/flox)) mice, mice developed SCCs exclusively on the tongue as early as 2 weeks after tamoxifen induction, concomitant with a remarkable activation of the mammalian target of rapamycin (mTOR) signaling pathway. The availability of this ras and p53 two-hit animal model system recapitulating HNSCC progression may provide a suitable platform for exploring novel molecular targeted approaches for the treatment of this devastating disease. Indeed, we show here that mTOR inhibition by the use of rapamycin is sufficient to halt tumor progression in this genetically defined oral cancer model system, thereby prolonging animal survival.
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PMID:Rapamycin prevents early onset of tumorigenesis in an oral-specific K-ras and p53 two-hit carcinogenesis model. 1943 1

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

FDA approval of the multitargeted, antiangiogenic tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib, and the serine and threonine mammalian target of rapamycin inhibitor, temsirolimus, has revolutionized the management of metastatic clear-cell renal-cell carcinoma (CC-RCC). The inability of these targeted therapies to provide durable complete responses, however, is a serious limiting factor to their clinical usefulness. Although immunotherapeutic approaches in advanced disease are increasingly regarded as a historical treatment paradigm, we propose that a fundamental understanding of immunobiology in CC-RCC can improve the selection of patients for high-dose intravenous interleukin 2 and facilitate the development of novel immunotherapeutic strategies. In our opinion, immunotherapeutic strategies have an important place in the management of advanced CC-RCC in the era of biological targeted therapy.
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PMID:Immunotherapeutic strategies in kidney cancer--when TKIs are not enough. 1954 65


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