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)

In order to study the relationship between mTOR (mammalian target of rapamycin) and tumorigenesis, we investigated the expression and activity of mTOR, and its substrates, alpha1, alpha2, beta1 and beta2 isoforms of p70S6 kinase (p70S6K) and eukaryotic initiation factor 4E binding protein-1 (4EBP-1) in oral squamous carcinoma and Hela cells using RT-PCR, immunohistochemistry, statistical analysis and Western blotting. The result of Western blots showed that in poorly differentiated oral squamous carcinoma, the expression level of mTOR and p70S6k increased in M phase, while that of 4EBP-1 decreased. The results of RT-PCR and immunohistochemistry assay are the same as that of Western blot. In Hela cells, the RT-PCR results showed that the level of mTOR mRNA did not change during the cell cycle. In M phase, the expression of alpha1, alpha2, beta1 and beta2 isoforms of p70S6K increased noticeably, while the expression of 4EBP-1 decreased. The immunoblot results in Hela cells were consistent with the RT-PCR results. Furthermore, the activity assays in Hela cells suggested that,in phase G2 and M, the activity of mTOR was maintained at a higher level than in any other phase, while 4EBP-1 decreased in phase M. These results may help in further investigations of the important role of mTOR in cell cycle and tumorigenesis.
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PMID:Expression and activity of mTOR and its substrates in different cell cycle phases and in oral squamous cell carcinomas of different malignant grade. 1692 14

The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-alpha (ERalpha) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERalpha as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.
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PMID:Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus. 1695 35

The year 2006 will mark a turning point in the daily management of patients with metastatic renal cell carcinoma. The impact of immunotherapy with interferon-alpha or interleukin-2 has been shown to be restricted to a minority of patients. The growing understanding of molecular mechanisms involved in the pathogenesis of the disease, especially clear-cell carcinoma, has led to the development of multiple targeted therapies with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor have been shown to improve the progression-free survival of patients in first- (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, an agent that inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.
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PMID:Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel. 1718 90

Endometrial cancer is one of the most common gynecologic malignancies. In patients with advanced or recurrent endometrial cancer survival is greatly diminished. Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Endocrine therapy provides a 10-20% response rate (RR) and survival of less than 1 year. Combination chemotherapy offers a RR of 40-60%, but the survival is still less than 1 year. The combination of cisplatin plus doxorubicin is the most commonly used regimen, but carboplatin plus paclitaxel represents an efficacious, low toxicity regimen in advanced or recurrent endometrial cancer. The addition of paclitaxel to cisplatin plus doxorubicin appears to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. At this time the focus of future research should be on the use of novel targeted agents, since it is unlikely that further significant advances could be made with chemotherapy and endocrine therapy. mTOR inhibitors represent a promising therapeutic strategy for endometrial cancer. Anti-HER-2/neu targeted therapy might be a novel and attractive therapeutic option in patients with biologically aggressive variants (uterine serous papillary carcinoma, clear cell carcinoma) of endometrial cancer. Research in better understanding the signal transduction pathways in endometrial carcinogenesis will allow the development of specific and selective molecularly targeted inhibitors.
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PMID:Systemic therapy in metastatic or recurrent endometrial cancer. 1719 49

A new era is developing in the understanding of the diagnosis, classification, and management of renal-cell carcinoma (RCC). Historically, RCC has been divided into subtypes on the basis of the histopathologic findings alone. Now, genetic alterations, nuclear characteristics, and clinical criteria are routinely incorporated into the classification. The greater use of axial imaging that began in the 1980s dramatically increased the incidence of RCC, but there has not been a decrease in the percentage of cases that are metastatic. Nevertheless, many incidental lesions prove to be benign, so there is renewed enthusiasm for biopsy before treatment is selected. Genetic conditions associated with RCC, such as Von Hippel Lindau and Birt-Hogg-Dube syndromes, along with genetic analyses of tumors, have provided considerable insight into the pathogenesis of these lesions. Renal-cell carcinoma is resistant to chemotherapy, and high-dose interleukin-2 is the only regimen currently approved by the Food and Drug Administration for the treatment of advanced RCC. Stem cell transplantation is an evolving therapy. The vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor-alpha pathways are promising targets for medical therapy of RCC. Bevacizumab, a monoclonal antibody that acts as a competitive blocker of the VEGF receptor; sorafenib, an oral well-tolerated tyrosine kinase inhibitor that blocks the intracellular second-messenger system associated with the VEGF receptor; sunitinib, a multitarget inhibitor of kinases associated with the VEGF and PDGF receptors; temsirolimus (CCI-779), a kinase blocker that inhibits the mammalian target of rapamycin pathway; and erlotinib, an inhibitor of the tyrosine kinases associated with the EGF receptor, have shown promise. Combinations of the above therapies and cytokines also are being investigated, as there may be synergistic effects.
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PMID:Update on the epidemiology and biology of renal cortical neoplasms. 1720 87

Autocrine tumour growth factor alpha (TGFalpha)/epidermal growth factor receptor (EGFR) stimulation in colorectal carcinoma (CRC) cells regulates cell adhesion and invasiveness via ribosomal protein S6 kinase (S6K) phosphorylation in pre-clinical studies. The aim of this study was to evaluate whether TGFalpha and EGFR expression might be correlated with a higher metastatic behaviour in human tumours. Paraffin-embedded material was retrospectively collected from 101 primitive CRCs including all stage IV patients at diagnosis treated at our Institution from 1999 to 2004 (50 cases, Group B) and 51 stage II-III control cases (Group A). EGFR and TGFalpha expression, together with signalling molecules (including signal transducer and activator of transcription [STAT3], serine-treonine kinase [Akt], mitogen-activated protein kinase [MAPK], mammalian target of rapamycin [mTOR] and S6K) in selected samples, was evaluated by immunohistochemistry using the EGFR Dako antibody. A total of 68/101 (67.3%) cases were EGFR positive and 79/101 (78.2%) cases were TGFalpha positive. EGFR/TGFalpha co-expression differed significantly (p = 0.02) between Group A and Group B tumours (23/51, 45.1% vs 34/50, 68.0%, respectively), whereas no differences in STAT, Akt, mTOR expression was evident between the two groups. Conversely, there was a significantly higher expression of phosphorylated S6K in stage IV cases (Group B) than in the controls (Group A; 70.4% vs 38.7%; p = 0.02). In agreement with in vitro data, EGFR, TGFalpha and S6K co-expression in human CRC was significantly higher in patients with advanced stage at diagnosis.
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PMID:Co-expression of EGF receptor, TGFalpha and S6 kinase is significantly associated with colorectal carcinomas with distant metastases at diagnosis. 1726 80

In animal models of cachexia, alterations in the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway have been demonstrated in atrophying skeletal muscles. Therefore, we assessed the activity of proteins in this pathway in muscle and liver biopsies from 16 patients undergoing pancreatectomy for suspect of carcinoma. Patients were divided in a non-cachectic or cachectic group according to their weight loss before operation. Extracts of skeletal muscle and liver tissue from eight cachectic patients with pancreas carcinoma and eight non-cachectic patients were analysed by Western blotting using pan- and phospho-specific antibodies directed against eight important signal transduction proteins of the PI3-K/Akt pathway. Muscle samples from cachectic patients revealed significantly decreased levels of myosin heavy chain (-45%) and actin (-18%) in comparison to non-cachectic samples. Akt protein level was decreased by -55%. The abundance and/or phosphorylation of the transcription factors Foxo1 and Foxo3a were reduced by up to fourfold in muscle biopsies from cachectic patients. Various decreases of the phosphorylated forms of the protein kinases mTOR (-82%) and p70S6K (-39%) were found. In contrast to skeletal muscle, cachexia is associated with a significant increase in phosphorylated Akt level in the liver samples with a general activation of the PI3-K/Akt cascade. Our study demonstrates a cachexia-associated loss of Akt-dependent signalling in human skeletal muscle with decreased activity of regulators of protein synthesis and a disinhibition of protein degradation.
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PMID:Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia. 1733 95

Carcinoid and islet-cell carcinoma are often also known as low-grade neuroendocrine carcinomas. They are often slow-growing but can be resistant to standard therapy. While somatostatin analogues are often used to control hormonal syndromes, there is currently no therapy approved in the US for control of carcinoid tumor growth. For islet-cell carcinoma, streptozocin-based chemotherapy may induce tumor shrinkage, but second-line option are limited. This chapter reviews the molecular biology of neuroendocrine tumors, including the roles of MENIN, TSC2, NF-1, vHL, p53, bcl-2, bax, VEGF, IGF, PDGF, EGFR, and mTOR. Recently, there has been interest in developing molecularly targeted therapy for this group of diseases. Phase-II studies with imatinib, bevacizumab, sunitinib, gefitnib, temsirolimus, and everolimus (RAD001) have completed accrual. Encouraging results have been observed in studies with VEGF and mTOR inhibitors. Phase-III study of bevacizumab is planned in the US. Large-scale multinational phase-II and -III studies of everolimus are under way.
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PMID:Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. 1738 71

The macrolide fungicide rapamycin has shown significant antiproliferative action toward a variety of tumor types. In this study, we used BK5.erbB2 transgenic mice as an animal model to examine the therapeutic effect of rapamycin as a potential treatment for gallbladder cancer. Homozygous BK5.erbB2 mice overexpressing the wild-type rat erbB2 gene in basal epithelial cells of the gallbladder have an approximately 70% incidence of gallbladder adenocarcinoma by 2 to 3 months of age. Groups of mice ( approximately 2-3 months of age) were treated with rapamycin by i.p. injection (once daily for 14 days) and then sacrificed 24 h after the last treatment. Rapamycin significantly reduced the incidence and severity of gallbladder carcinoma in BK5.erbB2 mice in a dose-dependent manner. Tumors responsive to treatment exhibited a higher number of apoptotic cells. Furthermore, rapamycin treatment led to decreased levels of phosphorylated p70 S6 kinase (Thr(389)) in gallbladder tissue as assessed by both Western blot and immunofluorescence analyses. Finally, immunofluorescence staining revealed elevated phosphorylated Akt (Ser(473)) and phosphorylated mammalian target of rapamycin (mTOR; Ser(2448)) in human gallbladder cancer compared with normal gallbladder tissue. Based on our results using a novel genetically engineered mouse model and the fact that the Akt/mTOR pathway is activated in human gallbladder cancer, rapamycin and related drugs may be effective therapeutic agents for the treatment of human gallbladder cancer.
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PMID:Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model. 1744 93

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.
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PMID:Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells. 1756 86


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