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

Therapeutic targeting of integral biological pathways, including those involving vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), has produced robust clinical effects and revolutionised the treatment of metastatic renal-cell carcinoma (RCC). However, some patients are inherently resistant to these approaches and most, if not all, patients acquire resistance over time. As such, the biological basis for resistance to these targeted therapies and the clinical approach in this setting is of heightened interest. Emerging preclinical evidence suggests resistance is mediated via tumour and environmental changes, which allow for continued perfusion and tumour growth that is less reliant on VEGF. Furthermore, elements upstream of receptor blockade, such as hypoxia-inducible factor (HIF) and protein kinase B (AKT), in addition to pathways independent of VEGF or mTOR, could drive tumour growth despite adequate target blockade. These considerations provide a rational basis for combination or sequential therapy targeting these elements. Clinical data support activity of several agents in resistant patient populations, with large-scale clinical trials ongoing to more thoroughly test several postulations regarding the optimum clinical approach.
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PMID:Resistance to targeted therapy in renal-cell carcinoma. 1979 51

Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001). Immunohistochemical analysis of urothelial carcinoma samples found loss of PTEN protein expression (36.4%, n = 11) and elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents.
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PMID:Activation of the PI3K/AKT pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models. 1984 58

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.
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PMID:Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells. 1985 12

Immunodeficient animal models are invaluable tools to investigate the metastatic propensity of human tumours. However residual immune responses, in particular natural killer (NK) cells, severely hamper the traffic and growth of human tumour cells. We studied whether a genetically modified mouse host lacking T, B and NK immunity allowed an improved expression of the metastatic phenotype of malignant human tumours. Metastatic spread of a panel of human sarcoma cell lines was studied in double knockout Rag2(-/-);gammac(-/-) mice in comparison with NK-depleted nude mice. Rag2(-/-);gammac(-/-) mice receiving intravenous (i.v.) or subcutaneous (s.c.) human sarcoma cell lines developed extensive multiorgan metastases. Metastatic efficiency in Rag2(-/-);gammac(-/-) was superior than in nude mice in terms of both metastatic sites and metastasis number. Metastatic growth in Rag2(-/-);gammac(-/-) mice was faster than that in nude mice, thus allowing an earlier metastasis evaluation. Most human sarcomas metastasised in the liver of Rag2(-/-);gammac(-/-) mice, a kind of organ preference undetectable in nude mice and specific of sarcomas, as several carcinoma cell lines failed to colonise the liver of Rag2(-/-);gammac(-/-) mice, independently of their metastatic spread to other sites. In vitro analysis of the molecular mechanisms of liver metastasis of sarcomas implicated liver-produced growth and motility factors, in particular the insulin-like growth factor (IGF) axis. NVP-BEZ235, a specific inhibitor of downstream signal transduction targeting PI3K and mTOR, strongly inhibited liver metastasis of human sarcoma cells. In conclusion, the Rag2(-/-);gammac(-/-) mouse model allowed the expression of human metastatic phenotypes inapparent in conventional immunodeficient mice and the preclinical testing of appropriate targeted therapies.
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PMID:High metastatic efficiency of human sarcoma cells in Rag2/gammac double knockout mice provides a powerful test system for antimetastatic targeted therapy. 2003 88

Inflammatory bowel disease (IBD) is a high-risk condition for human colorectal cancer. However, our mechanistic understanding of the link between inflammation and tumorigenesis in the colon is limited. Here we established a novel mouse model of colitis-associated cancer by genetically inactivating signal transducer and activator of transcription 3 (Stat3) in macrophages, with partial deletion in other myeloid and lymphoid cells. Inflammation developed in the colon of mutant mice spontaneously, and tumor lesions, including invasive carcinoma, arose in the inflamed region of the intestine with a frequency similar to that observed in human IBD patients. The development of both inflammation and tumors in the mutant mice required the presence of microflora. Indeed, inflammation was associated with disruption of colonic homeostasis, fulminant epithelial/tumor cell proliferation, and activation of the mammalian target of rapamycin (mTOR)-Stat3 pathway in epithelial and tumor cells. The activation of this pathway was essential for both the excess proliferation of epithelial/tumor cells and the disruption of colonic homeostasis in the mutant mice. Notably, a similar abnormal up-regulation of mTOR-Stat3 signaling was consistently observed in the colonic epithelial cells of human IBD patients with active disease. These studies demonstrate a novel mouse model of IBD-colorectal cancer progression in which disrupted immune regulation, mTOR-Stat3 signaling, and epithelial hyperproliferation are integrated and simultaneously linked to the development of malignancy.
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PMID:A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. 2004 77

We examined whether mTOR inhibition by RAD001 (Everolimus) could be therapeutically efficacious in the treatment of bladder cancer. RAD001 markedly inhibited proliferation of nine human urothelial carcinoma cell lines in dose- and sensitivity-dependent manners in vitro. FACS analysis showed that treatment with RAD001 for 48 h induced a cell cycle arrest in the G(0)/G(1) phase in all cell lines, without eliciting apoptosis. Additionally, RAD001 significantly inhibited the phosphorylation of S6 downstream of mTOR and VEGF production in all cell lines. We also found tumor weights from nude mice bearing human KU-7 subcutaneous xenografts treated with RAD001 were significantly reduced as compared to placebo-treated mice. This tumor growth inhibition was associated with significant decrease in cell proliferation rate and angiogenesis without changes in cell death. In conclusion inhibition of mTOR signaling in bladder cancer models demonstrated remarkable antitumor activity both in vitro and in vivo. This is the first study showing that RAD001 could be exploited as a potential therapeutic strategy in bladder cancer.
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PMID:Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer. 1994 4

Aberrant expression and mutations of thyroid hormone receptor genes (TRs) are closely associated with several types of human cancers. To test the hypothesis that TRs could function as tumor suppressors, we took advantage of mice with deletion of all functional TRs (TRalpha1(-/-)TRbeta(-/-) mice). As these mice aged, they spontaneously developed follicular thyroid carcinoma with pathological progression from hyperplasia to capsular invasion, vascular invasion, anaplasia and metastasis to the lung, similar to human thyroid cancer. Detailed molecular analysis revealed that known tumor promoters such as pituitary tumor-transforming gene were activated and tumor suppressors such as peroxisome proliferator-activated receptor gamma and p53 were suppressed during carcinogenesis. In addition, consistent with the human cancer, AKT-mTOR-p70(S6K) signaling and vascular growth factor and its receptor were activated to facilitate tumor progression. This report presents in vivo evidence that functional loss of both TRalpha1 and TRbeta genes promotes tumor development and metastasis. Thus, TRs could function as tumor suppressors in a mouse model of metastatic follicular thyroid cancer.
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PMID:Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma. 2006 85

Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.
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PMID:Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. 2008 Jun 88

Kaempferol, a dietary cancer chemopreventive polyphenol, has been reported to trigger apoptosis in several tumor histotypes, but the mechanism underlying this phenomenon is not fully understood. Here, we demonstrate that in HeLa cells, kaempferol induces energetic failure due to inhibition of both glucose uptake and Complex I of the mitochondrial respiratory chain. As adaptive response, cells activate autophagy, the occurrence of which was established cytofluorometrically, upon acridine orange staining, and immunochemically, by following the increase of the autolysosome-associated form of the microtubule-associated protein light chain 3 (LC3-II). Autophagy is an early and reversible process occurring as survival mechanisms against apoptosis. Indeed, chemical inhibition of autophagy, by incubations with monensin, wortmannin, 3-methyladenine, or by silencing Atg5, significantly increases the extent of apoptosis, which takes place via the mitochondrial pathway, and shortens the time in which the apoptotic markers are detectable. We also demonstrate that autophagy depends on the early activation of the AMP-activated protein kinase (AMPK)/mTOR-mediated pathway. The overexpression of dominant negative AMPK results in a decrease of autophagic cells, a decrement of LC3-II levels, and a significant increase of apoptosis. Experiments performed with another carcinoma cell line yielded the same results, suggesting for kaempferol a unique mechanism of action.
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PMID:Carcinoma cells activate AMP-activated protein kinase-dependent autophagy as survival response to kaempferol-mediated energetic impairment. 2008 95

Ru(eta6-arene) complexes of epidermal growth factor receptor (EGFR) inhibiting tyrphostins 1a and 1b were prepared, characterized and tested for DNA interaction and bioactivity in four human tumor cell lines. The intrinsic cytotoxicity and cell line selectivity of o-hydroxyanisol 1a was greatly enhanced in its Ru(eta6-p-cymene) complex 2a and in its Ru(eta6-toluene) complex 3a. Complex 2a was particularly efficacious against multi-drug resistant EGFR(+) MCF-7/Topo breast carcinoma cells and also against mTOR-dependent EGFR(-) HL-60 leukemia cells. Complex 3a showed enhanced activity only against 518A2 melanoma cells and HL-60 cells, which are both known to express the mTOR protein. DNA was strongly metallated (ca. 1.7-2%) by all new Ru complexes without undergoing topological changes. Apparently, by complexation to Ru fragments tyrphostin derivatives can address additional biological targets in a manner instrumental to antitumoral strategies.
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PMID:(Arene)Ru(II) complexes of epidermal growth factor receptor inhibiting tyrphostins with enhanced selectivity and cytotoxicity in cancer cells. 2014 40


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