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)

Hypoxia triggers a reversible inhibition of protein synthesis thought to be important for energy conservation in O2-deficient environments. The mammalian target of rapamycin (mTOR) pathway integrates multiple environmental cues to regulate translation in response to nutrient availability and stress, suggesting it as a candidate for O2 regulation. We show here that hypoxia rapidly and reversibly triggers hypophosphorylation of mTOR and its effectors 4E-BP1, p70S6K, rpS6, and eukaryotic initiation factor 4G. Hypoxic regulation of these translational control proteins is dominant to activation via multiple distinct signaling pathways such as insulin, amino acids, phorbol esters, and serum and is independent of Akt/protein kinase B and AMP-activated protein kinase phosphorylation, ATP levels, ATP:ADP ratios, and hypoxia-inducible factor-1 (HIF-1). Finally, hypoxia appears to repress phosphorylation of translational control proteins in a manner analogous to rapamycin and independent of phosphatase 2A (PP2A) activity. These data demonstrate a new mode of regulation of the mTOR pathway and position this pathway as a powerful point of control by O2 of cellular metabolism and energetics.
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PMID:A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. 1277 72

Continuing progress is being made in understanding the regulation of pancreatic acinar cell function by receptor-activated intracellular signaling mechanisms. Knowledge of how ligands interact at the molecular level with their receptors and activate heterotrimeric G proteins is increasing. In addition to inositol trisphosphate, intracellular messengers include cyclic ADP ribose, nicotinic acid adenine dinucleotide phosphate, arachidonic acid, and diacylglycerol. Ca signaling involves the interaction of inositol trisphosphate, cyclic ADP ribose, and nicotinic acid adenine dinucleotide phosphate with distinct subcellular Ca stores. Ca signals ultimately induce exocytosis of zymogen granules and identification of the proteins involved on the granule and plasma membrane, and understanding of their roles is continuing. Other receptor-activated signaling pathways primarily regulate nonsecretory events. Considerable progress has been made in understanding how the mammalian target of rapamycin pathway regulates protein synthesis through translation factors and ribosomal proteins. Other pathways in acinar cells include the mitogen-activated protein kinases, the tyrosine kinases, and the transforming growth factor-beta-Smad pathways.
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PMID:Receptor biology and intracellular regulatory mechanisms in pancreatic acinar cells. 1703 29

Expansion of the vasa vasorum network has been observed in a variety of systemic and pulmonary vascular diseases. We recently reported that a marked expansion of the vasa vasorum network occurs in the pulmonary artery adventitia of chronically hypoxic calves. Since hypoxia has been shown to stimulate ATP release from both vascular resident as well as circulatory blood cells, these studies were undertaken to determine if extracellular ATP exerts angiogenic effects on isolated vasa vasorum endothelial cells (VVEC) and/or if it augments the effects of other angiogenic factors (VEGF and basic FGF) known to be present in the hypoxic microenvironment. We found that extracellular ATP dramatically increases DNA synthesis, migration, and rearrangement into tube-like networks on Matrigel in VVEC, but not in pulmonary artery (MPAEC) or aortic (AOEC) endothelial cells obtained from the same animals. Extracellular ATP potentiated the effects of both VEGF and bFGF to stimulate DNA synthesis in VVEC but not in MPAEC and AOEC. Analysis of purine and pyrimidine nucleotides revealed that ATP, ADP and MeSADP were the most potent in stimulating mitogenic responses in VVEC, indicating the involvement of the family of P2Y1-like purinergic receptors. Using pharmacological inhibitors, Western blot analysis, and Phosphatidylinositol-3 kinase (PI3K) in vitro kinase assays, we found that PI3K/Akt/mTOR and ERK1/2 play a critical role in mediating the extracellular ATP-induced mitogenic and migratory responses in VVEC. However, PI3K/Akt and mTOR/p70S6K do not significantly contribute to extracellular ATP-induced tube formation on Matrigel. Our studies indicate that VVEC, isolated from the sites of active angiogenesis, exhibit distinct functional responses to ATP, compared to endothelial cells derived from large pulmonary or systemic vessels. Collectively, our data support the idea that extracellular ATP participates in the expansion of the vasa vasorum that can be observed in hypoxic conditions.
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PMID:Extracellular ATP is a pro-angiogenic factor for pulmonary artery vasa vasorum endothelial cells. 1807 15

The role of altered mitochondria function has recently emerged as an important mechanism for the development of diabetic complications. Altered mitochondria function has also been implicated in the ageing process, defective insulin secretion, hypertension, arteriosclerosis, ischemia-reperfusion injury and apoptosis. Normally, the mitochondria are associated with ATP production using primarily pyruvate as the substrate, but recent reports indicate that tissue specific preferences exist. Also, the mitochondria are a substantial source of superoxide production, preferentially during states of elevated intracellular glucose concentrations. The mitochondria function is regulated by several factors including nitric oxide, oxidative stress, mammalian target of rapamycin, ADP and P(i) availability, which result in a complex regulation of ATP production and oxygen consumption, but also superoxide generation. These factors seem to be tissue specific, which warrants a more diverse mechanistic model applying to that specific tissue or cell type. This review presents the basic functions of the mitochondria and focuses on the complex interplay between oxidative stress, nitric oxide and uncoupling proteins in regulating mitochondria function with special focus on diabetes-induced alterations occurring on the mitochondria level.
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PMID:Diabetes, oxidative stress, nitric oxide and mitochondria function. 1944 97

Triple-negative [estrogen receptor (ER)-/progesterone receptor (PR)-/HER2-] breast cancers account for ~15% of overall breast cancers. Triple-negative breast cancers demonstrate a panel of specific molecular alterations including a high rate of p53 mutations, frequent loss of function of BRCA1, phosphatase and tensin homolog (PTEN) loss and a specific panel of tyrosine kinase activation [fibroblast growth factor receptor 2 (FGFR2)]. This molecular entity is considered as sensitive to chemotherapy in the adjuvant setting. When metastatic, the disease is usually aggressive and drug resistant, leading to cancer death within 18 months for the majority of patients. There is no evidence from randomized trials that triple-negative breast cancers have a different sensitivity to specific chemotherapy compared with other molecular classes. Similar findings have been reported for bevacizumab. Several recent research efforts have focused on this entity in the last few years. DNA alkylating agents have shown promising activity in the neoadjuvant setting, but no evidence from a phase III trial currently supports its use. Several targeted therapies are also being successfully developed. Poly(ADP ribose) polymerase 1 (PARP1) inhibitors induce tumor response as a single agent in BRCA1-mutated breast cancer, and could sensitize cisplatin in the whole triple negative population. Several other targeted agents are being developed in this setting, including epidermal growth factor receptor (EGFR), FGFR2, mammalian target of rapamycin (mTOR) and NOTCH inhibitors.
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PMID:Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? 2094 32

Tanshinone IIA (Tan IIA; 14,16-epoxy-20-nor-5(10),6,8,13,15-abietapentaene-11,12-dione), a phytochemical derived from the roots of Salvia miltiorrhiza BUNGE, has been reported to posses anti-angiogenic, anti-oxidant, anti-inflammatory and apoptotic activities. However, the cancer growth inhibitory/cytocidal effects and molecular mechanisms in prostate cancer cells have not been well studied. In the present study, we demonstrate that Tan IIA significantly decreased the viable cell number of LNCaP (phosphate and tensin homolog (PTEN) mutant, high AKT, wild type p53) prostate cancer cells more sensitively than against the PC-3 (PTEN null, high AKT, p53 null) prostate cancer cells. Tan IIA significantly increased TdT-mediated dUTP nick-end labeling (TUNEL) positive index and sub-G1 DNA contents of treated cells, consistent with apoptosis. Tan IIA treatment led to cleavage activation of pro-caspases-9 and 3, but not pro-caspase-8, and cleavage of poly (ADP ribose) polymerase (PARP), a caspase-3 substrate. Additionally, Tan IIA treatment induced cytochrome c release from the mitochondria into the cytosol and reduced mitochondrial membrane potential and suppressed the expression of mitochondria protective Bcl-2 family protein Mcl-1(L). Tan IIA reduced the expression of phosphoinositide 3-kinase (PI3K) p85 subunit, and the phosphorylation of AKT and mammalian target of rapamycin (mTOR) in a concentration-dependent manner. Moreover, the combination of Tan IIA and LY294002, a specific PI3K inhibitor, enhanced PARP cleavage of LNCaP and PC-3, but not in MDA-MB-231 breast cancer cells which do not contain detectable active AKT. The findings suggest that Tan IIA-induced apoptosis involves mitochondria intrinsic caspase activation cascade and an inhibition of the PI3K/AKT survival pathway.
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PMID:Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway. 2104 7

Tumor resistance remains a major clinical challenge. Numerous pathways are under investigation to determine how best to target therapies to specific mutations in tumor biology and circumvent resistance. Agents in development include inhibitors of the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) pathway, such as iniparib, olaparib, and veliparib; the PI3K/Akt/mTOR pathway inhibitor everolimus; and the Src family tyrosine kinase inhibitor dasatinib. Research is ongoing to determine whether patients with specific biochemical attributes, such as the presence of a BRCA1 or BRCA2 mutation, will have a better response to targeted therapy and whether targeted agents act synergistically with chemotherapeutic agents.
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PMID:Novel agents and future directions for refractory breast cancer. 2160 Mar 81

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.
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PMID:Promising molecular targeted therapies in breast cancer. 2171 84

The modern approach to management of metastatic breast cancer (MBC) is centred on individualizing treatment to best suit the patient's breast cancer characteristics (molecular subtype, disease burden and prognostic markers), as well as the patient's clinical history (co-morbidities, prior therapies and social factors). The wealth of treatments available has heightened the complexity of tailored patient care that in turn allows better optimization of treatment efficacy and quality of life. There are promising developments in the management of estrogen receptor (ER)-positive breast cancer, particularly with respect to overcoming resistance with dual targeting of the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin and ER-signalling pathways. A central focus in the management of triple negative breast cancer has been through efforts to identify novel therapeutic targets in this disease subgroup. Next-generation sequencing approaches have begun to reveal how breast cancer somatic mutational heterogeneity between tumours with the same histopathological subtype is likely to impede efforts to identify novel common therapeutic targets. The most successful example of targeted therapy in MBC is the targeting of human epidermal growth factor receptor 2 (HER2) by trastuzumab. Dual and irreversible HER2/epidermal growth factor receptor targeting and attenuation of downstream resistance pathways also appear promising in HER2-positive trastuzumab-refractory breast cancer. Targeted therapy with antiangiogenic agents shows clinical activity, but the balance between efficacy, toxicity and cost remains a topic of debate, emphasizing the unmet need for a predictive biomarker of response to this class of drug. Poly(ADP ribose) polymerase(PARP) inhibitors appear to have clinically meaningful activity in BRCA germline mutant breast cancer. Activity of PARP inhibitors in other breast cancer subgroups is yet to be clearly defined. Novel chemotherapy agents show marginally superior efficacy, at a cost of a moderate increase in toxicity. Bone-modifying drugs expand supportive care options; again, better permitting individualization of treatment choice. The future management of MBC will increasingly focus on stratifying therapeutics based on individualized-tumour molecular aberrations.
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PMID:Recent developments in treatment stratification for metastatic breast cancer. 2203 12

The discovery of the molecular processes involved in cancer development has led to the design of an array of targeted agents. These agents, directed to specific proteins in the machinery of cancer cells, interfere with vital cascades involved in cell invasion, metastasis, apoptosis, cell-cycle control and angiogenesis. In breast cancer, the main pathways studied and targeted by drugs are the HER2 pathway, EGFR, VEGF, PI3K/Akt/mammalian target of rapamycin (PI3K-M-Tor), IGF/IGFR, poly(ADP ribose) polymerase 1, HDAC and many others. In this review, we present the most promising studies of these new targeted therapies and novel combination of targeted therapies with cytotoxic agents for the treatment of breast cancer patients.
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PMID:Novel targeted agents for the treatment of advanced breast cancer. 2257 14


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