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)

Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. This study analyzed the soluble factors secreted by lung cancer cells, which are responsible for increasing osteoclast differentiation. Addition of recombinant human interleukin-8 (rhIL-8), present in large amounts in A549-conditioned medium (CM) and NCI-H460-CM, mimicked the inductive effect of A549-CM and NCI-H460-CM on osteoclastogenesis. In contrast, depletion of interleukin-8 (IL-8) from A549-CM and NCI-H460-CM decreased the osteoclastogenesis-inductive properties of A549-CM and NCI-H460-CM. Induction of osteoclast differentiation by lung cancer-derived-CM and rhIL-8 was associated with increased phospholipase D (PLD) activation, and the activations of protein kinase C (PKC) alpha/betaII, extracellular signal-regulated kinase (ERK) 1/2 and AKT/the mammalian target of rapamycin (mTOR). Blocking PLD by a specific inhibitor significantly decreased osteoclast formation by inhibiting PKCs activation and subsequently attenuating the phosphorylation of ERK1/2. PLD inhibitor also completely decreased AKT and mTOR phosphorylation, whereas phosphatidylinositol-3-kinase (PI3K) inhibitor only partially decreased mTOR phosphorylation, suggesting that mTOR activation by PLD is through both PI3K/AKT-dependent and PI3K/AKT-independent manner. In addition, blocking AKT and ERK1/2 by a specific inhibitor also suppressed lung cancer-derived-CM and rhIL-8-induced osteoclast differentiation. Moreover, treatment of peripheral blood mononuclear cells with sera from invasive lung cancer patients increased the formation of osteoclasts. Our study suggests that IL-8 or IL-8-mediated PLD/PKC/ERK1/2 or PLD/AKT signaling is an attractive therapeutic target for osteolytic bone metastases in lung cancer patients.
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PMID:Phospholipase D signaling pathway is involved in lung cancer-derived IL-8 increased osteoclastogenesis. 2010 2

Subependymal giant cell astrocytomas (SEGAs) are rare brain tumors associated with tuberous sclerosis complex (TSC), a disease caused by mutations in TSC1 or TSC2, resulting in enhancement of mammalian target of rapamycin (mTOR) activity, dysregulation of cell growth, and tumorigenesis. Signaling via mTOR plays a role in multifaceted genomic responses, but its effectors in the brain are largely unknown. Therefore, gene expression profiling on four SEGAs was performed with Affymetrix Human Genome arrays. Of the genes differentially expressed in TSC, 11 were validated by real-time PCR on independent tumor samples and 3 SEGA-derived cultures. Expression of several proteins was confirmed by immunohistochemistry. The differentially-regulated proteins were mainly involved in tumorigenesis and nervous system development. ANXA1, GPNMB, LTF, RND3, S100A11, SFRP4, and NPTX1 genes were likely to be mTOR effector genes in SEGA, as their expression was modulated by an mTOR inhibitor, rapamycin, in SEGA-derived cells. Inhibition of mTOR signaling affected size of cultured SEGA cells but had no influence on their proliferation, morphology, or migration, whereas inhibition of both mTOR and extracellular signal-regulated kinase signaling pathways led to significant alterations of these processes. For the first time, we identified genes related to the occurrence of SEGA and regulated by mTOR and demonstrated an effective modulation of SEGA growth by pharmacological inhibition of both mTOR and extracellular signal-regulated kinase signaling pathways, which could represent a novel therapeutic approach.
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PMID:Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications. 2013 20

Lumican is a member of a small leucine-rich proteoglycan (SLRP) family and it regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. Lumican expression was reported in various kinds of tumor cells. Lumican inhibits the growth of melanoma cells, but the lumican in pancreatic cancer correlated with an advanced stage and retroperitoneal and duodenal invasion. In this study, we clarified whether the enhanced expression of lumican contributes to cellular attachment, growth, colony formation, migration and invasion. HEK 293 cell, stably transfected with lumican cDNA synthesized and secreted a 50 kDa lumican protein at high levels in culture medium. The cells showed a polygonal appearance with long projections and the degree of adhesion of the cells to fibronectin was lower than that of empty vector transfected control cells (mock cells). In contrast, the degree of adhesion of the cells to type I collagen was not different from that of mock cells. The expression levels of alpha5 integrin, the major integrin subunit for fibronectin, were lower in lumican-transfected HEK cells than in mock cells. Furthermore, lumican-transfected HEK cells showed reduced growth rates in vitro and did not form colonies in soft agar. Phosphorylation of AKT, extracellular signal-regulated kinase (ERK) 1/2 and mammalian target of rapamycin (mTOR) decreased in the lumican-transfected HEK cells. Cell migration and invasion were not altered in lumican-transfected HEK cells and mock cells. These findings indicate that the 50kDa lumican protein plays important roles in the inhibition of HEK cell attachment and growth, and it might inhibit the activation of integrin pathways.
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PMID:Enhanced expression of lumican inhibited the attachment and growth of human embryonic kidney 293 cells. 2013 70

The mammalian target of rapamycin (mTOR), a master regulator of translation initiation, has recently emerged as an attractive therapeutic target for cancer therapy. It has been demonstrated that mTOR inhibitors activate several cell survival pathways including phosphatidyl inositol 3-kinase/serine or threonine-specific protein kinase Akt and mitogen-activated protein kinase or extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase while suppressing mTOR signaling in different types of cancer cell lines and human tumor samples and thus make the cancer cells acquire resistance to the mTOR-targeted therapy. However, these cancer cells may be more dependent on (or addicted to) these survival pathways after receiving the mTOR-targeted therapy. It can be assumed that the combination of mTOR inhibitor and the suppressor of these survival pathways might achieve greater efficacy in inhibiting the growth of cancer cells. In this article we discuss the results of many pre-clinical and clinical studies of mTOR targeted therapy, with an emphasis of its effect against the non-small cell lung cancer.
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PMID:[Mammalian target of rapamycin inhibitors for the targeted therapy of non-small cell lung cancer]. 2045 May 58

The dismal prognosis of glioblastoma (GB) indicates the urgent need for new therapies for these tumors. Heat shock protein 90 (HSP90) inhibitors induce the proteasome-mediated degradation of many oncogenic client proteins involved in all of the hallmark characteristics of cancer. Here, we explored the mechanistic potential of the potent synthetic diarylisoxazole amide resorcinol HSP90 inhibitor, NVP-AUY922, in adult and pediatric GB. In vitro antiproliferative potency (nanomolar range) was seen in both adult and pediatric human GB cell lines with different molecular pathologies. A cytostatic effect was observed in all GB lines; more apoptosis was observed at lower concentrations in the SF188 pediatric GB line and at 144 hours in the slower growing KNS42 pediatric GB line, as compared with the adult GB lines U87MG and SF268. In vitro combination studies with inhibitors of phosphoinositide 3-kinase/mammalian target of rapamycin (PI-103) or mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (PD-0325901) supported the hypothesis that sustained inhibition of ERK up to 72 hours and at least temporary inhibition of AKT were necessary to induce apoptosis in GB lines. In athymic mice bearing established s.c U87MG GB xenografts, NVP-AUY922 (50 mg/kg i.p x 3 days) caused the inhibition of ERK1/2 and AKT phosphorylation and induced apoptosis, whereas 17-AAG used at maximum tolerated dose was less effective. NVP-AUY922 antitumor activity with objective tumor regression resulted from antiproliferative, proapoptotic, and antiangiogenic effects, the latter shown by decreased microvessel density and HIF1alpha levels. Our results have established a mechanistic proof of concept for the potential of novel synthetic HSP90 inhibitors in adult and pediatric GB, alone or in combination with phosphoinositide 3-kinase/mammalian target of rapamycin and mitogen-activated protein/ERK kinase inhibitors.
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PMID:Mechanistic evaluation of the novel HSP90 inhibitor NVP-AUY922 in adult and pediatric glioblastoma. 2045 19

Tumor-induced angiogenesis is essential for invasive growth and hematogenous metastasis of adenoid cystic carcinoma (ACC), a highly aggressive neoplasm mostly occurring in salivary glands. Previous studies have indicated that strategies directed against angiogenesis will help develop new therapeutic agents for ACC. The Chinese folk medicine licorice has been used for years as a natural remedy for angiogenesis-related diseases. In this study, we examined the effects of isoliquiritigenin (ISL), a flavonoid isolated from licorice, on the growth and viability of ACC cells and observed a concentration-dependent (0-20 microM) inhibition of cell growth without cell death at 24 h. In a further mimic coculture study, ISL effectively suppressed the ability of ACC cells to induce in vitro proliferation, migration, and tube formation of human endothelial hybridoma (EAhy926) cells as well as ex vivo and in vivo angiogenesis, whereas it exerted no effect on EAhy926 cells when added directly or in the presence of vascular endothelial growth factor (VEGF). The data also showed that the specific suppression of tumor angiogenesis by ISL was caused by down-regulation of mammalian target of rapamycin (mTOR) pathway-dependent VEGF production by ACC cells, correlating with concurrent activation of c-Jun NH(2)-terminal kinase (JNK) and inhibition of extracellular signal-regulated kinase (ERK). Most importantly, ISL also significantly decreased microvessel density within xenograft tumors, associating with the reduction of VEGF production and suppression of the mTOR pathway coregulated by JNK and ERK, as revealed by immunohistochemical studies and clustering analysis. Taken together, our results highlight the fact that ISL is a novel inhibitor of tumor angiogenesis and possesses great therapeutic potential for ACC.
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PMID:Mammalian target of rapamycin pathway promotes tumor-induced angiogenesis in adenoid cystic carcinoma: its suppression by isoliquiritigenin through dual activation of c-Jun NH2-terminal kinase and inhibition of extracellular signal-regulated kinase. 2048 54

Several studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non-small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G(2) arrest following irradiation and induced gammaH2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation.
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PMID:Targeting epidermal growth factor receptor-associated signaling pathways in non-small cell lung cancer cells: implication in radiation response. 2058 32

Autophagy is a regulated catabolic process triggered in cells deprived of nutrients or growth factors that govern nutrient uptake. Here, we report that autophagy is induced by cetuximab, a therapeutic antibody that blocks epidermal growth factor receptor function. Cancer cell treatment with cetuximab triggered autophagosome formation, conversion of microtubule-associated protein 1 light chain 3 from its cytoplasmic to membrane-associated form, and increased acidic vesicular organelle formation. Autophagy occurred when cetuximab inhibited the class I phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, but not when it inhibited only the mitogen-activated protein/extracellular signal-regulated kinase kinase/Erk pathway, and it was accompanied by decreased levels of hypoxia inducible factor-1 alpha (HIF-1alpha) and Bcl-2. Stable overexpression of a HIF-1alpha mutant prevented cetuximab-induced autophagy and decrease in Bcl-2 levels. Knockdown of autophagy regulator beclin 1 or cell treatment with autophagy inhibitor 3-methyladenine, a class III PI3K (hVps34) inhibitor, also inhibited cetuximab-induced autophagy. Furthermore, knockdown of beclin 1 or Atg7 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cetuximab-induced apoptosis. Mechanistic analysis argued that cetuximab acted by promoting an association between beclin 1 and hVps34, which was inhibited by overexpression of Bcl-2. Our findings suggest that the autophagy protects cancer cells from the proapoptotic effects of cetuximab.
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PMID:The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. 2063 5

Somatostatin analogues ameliorated many symptoms caused by neuroendocrine tumors (NET), but their antitumor activities are limited especially in non-functioning cases. An overactivation of signaling pathways under receptor tyrosine-kinase (RTK) has been recently demonstrated in some NET patients, but its details have remained largely unknown. Therefore, in this study, we immunolocalized therapeutic factors and evaluated the data to study the clinical significance of the molecules in non-functioning Japanese gastrointestinal NET. Fifty-two NET cases were available for examination in this study and expression of somatostatin receptor (sstr) 1, 2A, 2B, 3 and 5, activated form of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4-binding protein 1 (4EBP1), ribosomal protein s6 (S6), extracellular signal-regulated kinase (ERK) and insulin-like growth factor 1 receptor (IGF-1R) was evaluated using immunohistochemistry. We then studied the correlation among the immunohistochemical results of the individual cases using hierarchical clustering analysis. Results of clustering analysis demonstrated that NET cases were basically classified into Cluster I and II. Cluster I was associated with higher expression of sstr1, 2B and 3 and Cluster II was characterized by an activation of the PI3K/Akt pathway and IGF-1R and higher proliferative status. Cluster II was further classified into Cluster IIa and IIb. Cluster IIa was associated with higher expression of sstr1 and 5 and higher proliferative status and Cluster IIb was characterized by ERK activation. Hierarchical clustering analysis of immunoreactivity of the therapeutic factors can classify NET cases into three distinctive groups and the medical treatment may be determined according to this novel classification method for non-functioning NET patients.
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PMID:Novel classification based on immunohistochemistry combined with hierarchical clustering analysis in non-functioning neuroendocrine tumor patients. 2068 6

Activation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen-induced lung tumorigenesis, and therapies that target mTOR could be effective in the prevention or treatment of lung cancer. The biguanide metformin, which is widely prescribed for the treatment of type II diabetes, might be a good candidate for lung cancer chemoprevention because it activates AMP-activated protein kinase (AMPK), which can inhibit the mTOR pathway. To test this, A/J mice were treated with oral metformin after exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that are achievable in humans. mTOR was inhibited in lung tumors but only modestly. To test whether intraperitoneal administration of metformin might improve mTOR inhibition, we injected mice and assessed biomarkers in liver and lung tissues. Plasma levels of metformin were significantly higher after injection than oral administration. In liver tissue, metformin activated AMPK and inhibited mTOR. In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK), and mTOR. This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. Based on these data, we repeated the NNK-induced lung tumorigenesis study using intraperitoneal administration of metformin. Metformin decreased tumor burden by 72%, which correlated with decreased cellular proliferation and marked inhibition of mTOR in tumors. These studies show that metformin prevents tobacco carcinogen-induced lung tumorigenesis and support clinical testing of metformin as a chemopreventive agent.
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PMID:Metformin prevents tobacco carcinogen--induced lung tumorigenesis. 2081 Jun 71


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