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)

Increased cell proliferation, which is a hallmark of aggressive malignant neoplasms, requires a general increase in protein synthesis and a specific increase in the synthesis of replication-promoting proteins. Transient increase in the general protein synthesis rate, as well as preferential translation of specific mRNAs coding for growth promoting proteins (e.g. cyclin D1), takes place during normal mitogenic response. A number of extensively studied growth signal transduction pathways (Ras, PI3K, MAPK, mTOR-dependent pathways) activate the function and expression of various components of the translational machinery. In abnormal situations, constitutive activation of signal transduction pathways (e.g. oncogenic activation of Ras or Myc) leads to continuous upregulation of key elements of translational machinery. On the other hand, tumor suppressor genes (p53, pRb) downregulate ribosomal and tRNA synthesis, and their inactivation results in uncontrolled production of these translational components. During recent years, a significant effort has been dedicated to determining whether expression of translation factors is increased in human tumors using clinical biopsy specimens. The results of these studies indicate that expression of particular translation initiation factors is not always increased in human neoplasms. The pattern of expression is characteristic for a particular tumor type. For example, eIF-4E is usually increased in bronchioloalveolar carcinomas but not in squamous cell carcinomas of the lung. Interestingly, in certain highly proliferative and aggressive neoplasms (e.g. squamous cell carcinoma of the lung, melanoma), the expression of eIF-4E is barely detectable. These findings suggest that mechanisms for increasing general protein synthesis in various neoplasms differ significantly. Finally, the possibility of qualitative alterations in the translational machinery, rather than a simple increase in the activity of its components, is discussed along with the possibility of targeting those qualitative differences for tumor therapy.
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PMID:The role of translation in neoplastic transformation from a pathologist's point of view. 1509 73

Overexpression of inducible nitric oxide synthase (iNOS) has been reported in several human cancers, including esophageal squamous cell carcinoma (SCC). Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon carcinogen found in tobacco smoke and in the environment, induces cancer in multiple organ sites in animals and may be a causative agent for certain human cancers, such as esophageal cancer. In the present study, the effects of B[a]P on the induction of iNOS and the signaling pathways that lead to the induction were investigated in cultured rat esophageal epithelial (RE-149) cells. Treatment of RE-149 cells with B[a]P led to a marked increase in the expression of iNOS. The induction of iNOS by B[a]P was found to occur through an extracellular signal-regulated protein kinases (ERKs)-dependent pathway, since inhibition of ERKs by either pretreatment of RE-149 cells with PD98059, an inhibitor of ERKs upstream kinase MEK1/2, or overexpression of DN-ERK2, blocked the induction of iNOS by B[a]P. Furthermore, impairing nuclear factor-kappaB (NFkappaB) activation by either NEMO-BDBP, an NFkappaB specific inhibitor, or overexpression of DN-IkappaBalpha or IKK-KM markedly inhibited the expression of B[a]P-induced iNOS, suggesting that the NFkappaB pathway is also required for the induction of iNOS by B[a]P. In addition, treatment of RE-149 cells with either SB202190, a p38 kinase inhibitor, or c-JunN-terminal kinase inhibitor II, resulted in an increased induction of iNOS. Pretreatment of RE-149 cells with wortmannin, a PI-3K inhibitor, or with rapamycin, an mTOR/p70S6K pathway inhibitor, had no effect on the expression of iNOS. These results suggest that B[a]P initiates the signaling pathways leading to the induction of iNOS in cultured rat esophageal epithelial cells. In view of the potential role of iNOS in the development of esophageal SCC in humans, we speculate that the induction of iNOS by B[a]P may be one mechanism by which B[a]P could produce carcinogenic effects in the human esophagus.
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PMID:Differential requirement of signal pathways for benzo[a]pyrene (B[a]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells. 1571 51

Emerging knowledge on how the dysregulated function of signaling networks contributes to the malignant growth of squamous cell carcinoma of the head and neck (HNSCC) can now be exploited to identify novel mechanism-based anticancer treatments. In this regard, we have observed that persistent activation of the serine/threonine kinase Akt is a frequent event in HNSCC, and that blockade of its upstream kinase, 3'-phosphoinositide-dependent kinase 1, potently inhibits tumor cell growth. Akt promotes cell proliferation by its ability to coordinate mitogenic signaling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). This kinase, in turn, phosphorylates key eukaryotic translation regulators, including p70-S6 kinase and the eukaryotic translation initiation factor, 4E binding protein 1. Indeed, we show here that aberrant accumulation of the phosphorylated active form of S6, the most downstream target of the Akt-mTOR-p70-S6 kinase pathway, is a frequent event in clinical specimens from patients with HNSCC and their derived cell lines. Of interest, this enhanced level of the phosphorylated active form of S6 was rapidly reduced in HNSCC cell lines and HNSCC xenograft models at clinically relevant doses of rapamycin, which specifically inhibits mTOR. Furthermore, we observed that rapamycin displays a potent antitumor effect in vivo, as it inhibits DNA synthesis and induces the apoptotic death of HNSCC cells, ultimately resulting in tumor regression. These findings identify the Akt-mTOR pathway as a potential therapeutic target for HNSCC, and may provide the rationale for the early clinical evaluation of rapamycin and its analogues in patients with HNSCC.
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PMID:Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. 1626 20

The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma (SCC) of the head and neck. Most patients, however, do not respond or develop resistance to this agent. Mammalian target of rapamycin (mTOR) is involved in the pathogenesis of SCC of the head and neck (SCCHN). This study aimed to determine if targeting mTOR in combination with EGFR is effective in SCC, and to develop early pharmacodynamic markers of efficacy. Two SCC cell lines, one resistant (HEP2) and one of intermediate susceptibility (Detroit 562) to EGFR inhibitors, were xenografted in vivo and treated with an mTOR inhibitor (temsirolimus), an EGFR inhibitor (erlotinib) or a combination of both. Temsirolimus exerted superior growth arrest in both cell lines than erlotinib. The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line. Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration (FNA) biopsies early after treatment using phospho MAPK, Phospho-P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination, the only group where regressions were seen. In conclusion, an mTOR inhibitor showed antitumor activity in EGFR-resistant SCC cell lines. Marked antitumor effects were associated with dual pathway inhibition, which were detected by early FNA biopsies.
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PMID:Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. 1734 92

mTOR/p70S6K pathway is considered a central regulator in various malignant tumors, but its roles in esophageal squamous cell carcinoma (ESCC), which is a common cause of mortality in China, remain unknown. Here, we identify that the mTOR/p70S6K pathway is activated in ESCC; rapamycin and siRNA against mTOR rapidly inhibited expression of mTOR and the phosphorylation of its major downstream effectors, p70S6K and 4E-BP1, arrested cells in the G(0)/G(1) phase and induced apoptosis of ESCC cells. The findings may lay a foundation for making further investigations on the mTOR/p70S6K pathway as a potential target for ESCC therapy.
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PMID:An activated mTOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR. 1736 Jan 8

Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)-related family of protein kinases. Germ line-inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1(+/-) mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression.
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PMID:LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. 1817 96

Emerging evidence supporting the activation of the Akt-mammalian target of rapamycin (mTOR) signaling network in head and neck squamous cell carcinoma (HNSCC) progression has provided the rationale for exploring the therapeutic potential of inhibiting this pathway for HNSCC treatment. Indeed, rapamycin, a clinically relevant mTOR inhibitor, promotes the rapid regression of HNSCC-tumor xenografts in mice. However, rapamycin does not affect the growth of HNSCC cells in vitro, thus raising the possibility that, as for other cancer types, rapamycin may not target cancer cells directly but may instead act on a component of the tumor microenvironment, such as tumor-associated vasculature. Here, we used a retroinhibition approach to assess the contribution of cancer cell-autonomous actions of rapamycin to its antitumor activity in HNSCC. A rapamycin-resistant form of mTOR (mTOR-RR) was expressed in HNSCC cells while retaining the wild-type (rapamycin-sensitive) mTOR (mTOR-WT) alleles in host-derived endothelial and stromal cells. Expression of mTOR-RR prevented the decrease in phospho-S6 levels caused by rapamycin through mTOR in HNSCC cells but not in stromal cells, and rendered HNSCC xenografts completely resistant to the antitumoral activity of rapamycin. This reverse pharmacology strategy also enabled monitoring the direct consequences of inhibiting mTOR in cancer cells within the complex tumor microenvironment, which revealed that mTOR controls the accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and the consequent expression of vascular endothelial growth factor and a glucose transporter, Glut-1, in HNSCC cells. These findings indicate that HNSCC cells are the primary target of rapamycin in vivo, and provide evidence that its antiangiogenic effects may represent a downstream consequence of mTOR inhibition in HNSCC cells.
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PMID:A retroinhibition approach reveals a tumor cell-autonomous response to rapamycin in head and neck cancer. 1828 90

Although preclinical studies have suggested that farnesyltransferase inhibitors (FTI) have promising antitumor activity, clinical trials have shown that FTI activity in patients is actually limited. The mechanism that induces resistance to FTI treatment is still not fully understood. The FTI SCH66336 has been shown to induce apoptotic and antiangiogenic activities in a subset of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. We therefore investigated the mechanisms mediating resistance to the therapeutic activities of SCH66336 in HNSCC and NSCLC. Our various analyses showed that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of SCH66336 in HNSCC and NSCLC cells. Treatment with SCH66336 activated the IGF-IR/phosphatidylinositol 3-kinase/Akt pathway, leading to increased mammalian target of rapamycin (mTOR)-mediated protein synthesis of survivin in a subset of HNSCC and NSCLC cell lines that were insensitive to the apoptotic activities of the drug. Inhibition of IGF-IR, Akt, or mTOR or the knockdown of survivin expression abolished resistance to SCH66336 and induced apoptosis in the cells. Overexpression of survivin by the use of adenoviral vector protected SCH66336-sensitive HNSCC cells from the apoptotic activities of the drug. Our results suggest that expression of phosphorylated IGF-IR, phosphorylated Akt, phosphorylated mTOR, and survivin serves as biological markers of SCH66336 responsiveness in HNSCC and NSCLC cells and that SCH66336 induces survivin expression through an IGF-IR/Akt/mTOR-dependent pathway. Thus, combining inhibitors of IGF-IR, phosphatidylinositol 3-kinase/Akt, mTOR, or survivin with SCH66336 may be an effective anticancer therapeutic strategy for patients with HNSCC or NSCLC.
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PMID:Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression. 1831 83

The activation of the PI3K/Akt/mTOR pathway plays an important role in tumorigenesis and resistance to anticancer drugs. The aim of this study was to elucidate the role of the Akt/mTOR pathway in chemoresistance and the prognosis of patients with esophageal squamous cell carcinoma (ESCC) who received preoperative chemotherapy. We evaluated p-Akt and p-mTOR expression by immunohistochemistry in the surgical specimens of 143 ESCC (51 patients with and 92 without preoperative chemotherapy). In 37 patients of the former group, paired tissue samples obtained before and after chemotherapy were examined immunohistochemically. The incidence of p-Akt expression was higher in ESCC with than without chemotherapy (51.0 vs. 25.0%, p=0.0018). Although p-Akt expression was not associated with an advanced tumor stage, a comparison between before and after chemotherapy demonstrated an increased p-Akt expression during chemotherapy (p=0.0348). The p-Akt expression did not correlate with survival in ESCC without chemotherapy, but was associated with poor prognosis in those with chemotherapy (p=0.0058). In particular, an increased p-Akt expression during chemotherapy was associated with poor survival (p=0.0022). Notably, the p-mTOR expression did not correlate with p-Akt expression (p=0.1482). The depth of the tumor invasion, clinical response and p-Akt expression correlated with the prognosis of 51 ESCC with chemotherapy. A multivariate analysis showed that p-Akt expression was the only independent predictor of poor prognosis in ESCC patients with chemotherapy. p-Akt expression increases after chemotherapy in ESCC and a high expression correlates with poor prognosis. Our results suggest that the activation of Akt is a potentially useful therapeutic target in ESCC patients treated with chemotherapy.
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PMID:The activation of Akt during preoperative chemotherapy for esophageal cancer correlates with poor prognosis. 1842 64

Malignant tumors are exposed to various levels of hypoxic condition in vivo. It has been known that tumor cells under hypoxia are resistant to chemotherapies. To clarify the mechanism of the hypoxia-induced chemoresistance, we evaluated the effects of hypoxia on the resistance of oral squamous cell carcinoma (OSCC) cell lines to 5-fluorouracil (5-FU). OSCC cells were divided to two groups by the proliferation activity under hypoxic condition; hypoxia-resistant (HR) and hypoxia-sensitive (HS) cells. Growth of HS cells were inhibited by hypoxia and introduced to G(1) arrest in cell cycle. 5-FU effect on HS cell viability was markedly reduced in hypoxic condition without an induction of chemoresistant related protein, P-glycoprotein. However, proliferation, cell cycle, and 5-FU sensitivity of HR cells were not affected by hypoxia. Hypoxia-inducible factor (HIF)-1alpha was induced by hypoxia in all OSCC cell lines, but diminished in HS cells within 48h. Expression of p21 and p27 was strongly augmented and CyclinD expression was reduced by hypoxia in HS cells. However, the expression of these proteins was constitutive in HR cells during 48h hypoxic culture. Phosphorylation of mammalian target of rapamycin (mTOR) was reduced by hypoxia in HS cells. From these findings, we concluded that HS OSCC cells acquire 5-FU resistance under hypoxia by G(1)/S transition through an upregulation of cell cycle inhibitors.
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PMID:Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G(1) phase cell cycle arrest. 1871 Aug 19


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