Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokine-based immunotherapy was the only viable option in metastatic, nonresectable renal cell carcinoma (RCC) for many years. Systemic immunotherapy has become increasingly established as a standard therapy during the last 15 years. In this context, interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) turned out to be the most effective single agents in RCC. Subsequently, the approved subcutaneous application of these compounds was the preferred administration route in Germany. Response rates with cytokine combination therapy were almost similar to those of more aggressive concepts using additional chemotherapeutic agents.Currently, new compounds targeting specific signaling pathways are readily available and have passed clinical testing. Such small molecules like tyrosine kinase inhibitors, monoclonal antibodies, or the mTOR inhibitor CCI-779 may dramatically change the established concepts of systemic RCC treatment. This paper gives an overview of established, current, and evolving concepts of systemic therapy in RCC.
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PMID:[Systemic therapy of metastatic renal cell carcinoma]. 1662 45

Cytokine therapies have been the standard of care in metastatic renal cell carcinoma (RCC). However, these agents only provide clinical benefit to a small subset of patients and are associated with significant toxicity. A better understanding of the molecular biology of RCC has identified the vascular endothelial growth factor (VEGF) and platelet-derived growth factor signalling pathways as rational targets for anticancer therapy. The multitargeted receptor tyrosine kinase inhibitors sunitinib and sorafenib have both demonstrated improved efficacy as second-line therapy in patients with RCC. Sunitinib has also been shown to be effective in the first-line setting, and has recently received European Union approval as first-line treatment for advanced and/or metastatic RCC. There is also recent evidence that temsirolimus (an inhibitor of the mammalian target of rapamycin) and bevacizumab (a mAb targeted against VEGF) may provide benefits in the first-line treatment setting. These results confirm that inhibiting these tumour targets is a feasible approach to treatment and provides a more positive outlook for the future management of metastatic RCC.
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PMID:Treatment options in renal cell carcinoma: past, present and future. 1776 20

Cytokine-based therapeutic approaches using interferon (IFN) and interleukin 2 (IL-2) were conventionally applied for the treatment of progressive RCC. Caused by the limited effectiveness of cytokine-based approaches in advanced renal cell carcinoma, new substances were needed. Among these, the "targeted therapies", particularly the group of the tyrosine kinase inhibitors, are of main interest. At present, multikinase inhibitors and antiangiogenic agents (VEGFR, PDGFR-beta, and mTOR) are used in first- and second-line therapies of metastatic RCC in various clinical studies. This review presents and discusses the effectiveness of the most frequently used substances in mono- or combination regimes based on current data of the ASCO 2007.
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PMID:Novel therapeutic options in metastatic renal cancer - review and post ASCO 2007 update. 1878 79

Oral glucose uptake alters the function of immune cells and an elevation of systemic CXCL8 was described. Monocytes secrete high amounts of CXCL8 and therefore it was analyzed whether glucose or insulin upregulate monocytic CXCL8 release. Incubation of monocytes with insulin for 2h induced CXCL8 mRNA and secretion whereas glucose had no effect. Inhibition of the phosphatidylinositol 3-kinase by wortmannin or the mammalian target of rapamycin by rapamycin did not influence insulin-mediated CXCL8 induction. In contrast, blockage of the ERK-specific MAP kinase MEK with PD98059, that prevents phosphorylation of ERK1/ERK2, abrogated insulin-induced CXCL8 release in primary monocytes. To investigate the in vivo effect of oral glucose uptake, monocytes of healthy probands were isolated in the fasted state and 2h after glucose ingestion and CXCL8 mRNA and protein were increased in the latter. CXCL8 was also higher when determined in the cell lysate of leukocytes 2h after glucose uptake whereas plasma CXCL8 levels were significantly reduced. In summary, these data indicate that oral glucose uptake in insulin-sensitive adults is associated with elevated monocytic and reduced systemic CXCL8.
Cytokine 2008 Oct
PMID:Insulin induces monocytic CXCL8 secretion by the mitogenic signalling pathway. 1878 71

The mTOR signaling pathway plays a very important role in the transmission of signals for initiation of mRNA translation and protein expression in mammalian cells. mTOR activates various downstream effectors to promote initiation of cap-dependent mRNA translation and mediate pro-mitogenic and pro-survival signals. Recent evidence has implicated effectors of this signaling cascade in mRNA translation for interferon stimulated genes (ISGs). In addition, it was recently shown that AKT/mTOR-mediated signals play important roles in the generation of IFN-dependent antiviral and growth inhibitory responses, suggesting that mTOR and its effectors can mediate diverse biological responses, depending on the cellular context and the triggering stimuli. In this review, the regulatory effects of various growth suppressive cytokines on the mTOR pathway are summarized and the emerging new functions of mTOR are discussed.
Cytokine
PMID:Growth suppressive cytokines and the AKT/mTOR pathway. 1968 19

Renal cell carcinoma (RCC) is among the most resistant tumours to chemotherapy, radiotherapy and hormonal therapy. Cytokine therapy is effective in a small subset of patients, but it is associated with substantial toxicity and rarely benefits patients with extensive tumour burdens or adverse prognostic factors. Since 2005, clinical trials have shown significant clinical benefits for five molecularly targeted therapies in patients with advanced RCC. These agents constitute two mechanistic classes: (i) angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) ligand (bevacizumab, in combination with interferon-a) or VEGF receptors (sunitinib, sorafenib); and (ii) inhibitors of the mammalian target of rapamycin (mTOR) signalling (temsirolimus, everolimus). This review assesses the mechanistic distinctions and functional overlaps of these classes of agents, and discusses key characteristics of their respective clinical efficacy and side-effect profiles in patients with RCC, some of which might affect patient selection and treatment strategies. Current research is designed to optimize the use of these agents, as well as the development of new investigational therapies within these mechanistic classes. The differences and synergies are particularly important for understanding the best ways to integrate VEGF/VEGF receptor inhibitors and mTOR inhibitors for combination or sequential treatment of patients with advanced RCC.
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PMID:Vascular endothelial growth factor and mTOR pathways in renal cell carcinoma: differences and synergies of two targeted mechanisms. 2005 90

The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit "oncogene-addicted" growth, while they do display "cytokine-addicted" proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 hrs. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G(1) block, while paclitaxel triggered a G(2)/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not "oncogene-addicted" may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors.
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PMID:Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy. 2043 69

Obesity in human is an alarming major public health crisis worldwide and insulin resistance is a hallmark of it. The negative cross-talk between skeletal muscle and adipose tissue through adipokines is now accepted as one of the leading cause of insulin resistance. Chemerin is a novel adipokine previously reported to induce insulin resistance in primary human skeletal muscle cells. To investigate the role of chemerin in myogenesis, C2C12 cells were used and treated with chemerin in proliferation and differentiation stages. Our results showed that chemerin promoted proliferation and suppressed differentiation of C2C12 cells through extracellular-signal regulated kinase-1/2 (ERK1/2) and mammalian target of rapamycin (mTOR) signaling pathways, and these two pathways were interacted with each other in C2C12 cells treated with chemerin. It is concluded from this in vitro study that chemerin which expression is increased during myoblast differentiation appears to be able, likely in an autocrine/paracrine manner, to increase myoblast proliferation and decrease myoblast differentiation.
Cytokine 2012 Dec
PMID:Chemerin regulates proliferation and differentiation of myoblast cells via ERK1/2 and mTOR signaling pathways. 2290 99

Erythropoietin (EPO) and Stem Cell Factor (SCF) have partially distinct functions in erythroid cell development. The primary functions of EPO are to prevent apoptosis and promote differentiation, with a minor role as a mitogen. On the other hand SCF acts primarily as a mitogenic factor promoting erythroid cell proliferation with a minor role in inhibition of apoptosis. The concerted effects of these two growth factors are responsible for guiding initial commitment, expansion and differentiation of progenitors. The aim of the study was to identify signaling elements pertinent to translational control and elucidate whether both cytokines can contribute to protein translation providing some functional redundancy as seen with respect to apoptosis. The current study focused on non-apoptotic functions of SCF mediated through mTOR/p70S6 leading to protein translation and cell proliferation. We utilized a human primary erythroid progenitors and erythroblasts that are responsive to EPO and SCF to investigate the activation of mTOR/p70S6 kinases and their downstream effectors, the pathway primarily responsible for protein translation. We showed that mTOR, p70S6 kinases and their downstream signaling elements 4EBP1 and S6 ribosomal protein are all activated by SCF but not by EPO in primary erythroid progenitors. We also found that SCF is the sole contributor to activation of the protein translational machinery and activation of mTOR/p70S6 pathway is confined to the proliferative phase of erythroid differentiation program. Altogether these results demonstrate that unlike the survival function which is supported by both EPO and SCF protein translation essential for proliferation is governed by only SCF.
Cytokine 2013 Jan
PMID:Distinct functions of erythropoietin and stem cell factor are linked to activation of mTOR kinase signaling pathway in human erythroid progenitors. 2314 90

The eukaryotic translation initiation factor eIF4E is overexpressed in many human malignancies where it is typically a harbinger of poor prognosis. eIF4E is positioned as a nexus in post-transcriptional gene expression. To carry out these functions, eIF4E needs to bind the m(7)G cap moiety on mRNAs. It plays critical roles in mRNA translation, mRNA export, and most likely in mRNA stability as well. Through these activities, eIF4E coordinately modulates the expression of many transcripts involved in proliferation and survival. eIF4E function is controlled by interactions with protein cofactors in concert with many signaling pathways, including Ras, Mnk, Erk, MAPK, PI3K, mTOR, and Akt. This review describes the eIF4E activity and provides several examples of cellular control mechanisms. Further, we describe some therapeutic strategies in preclinical and clinical development.
J Interferon Cytokine Res 2013 May
PMID:The oncogene eIF4E: using biochemical insights to target cancer. 2347 59


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