Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human malignancies develop via a multi-step that involves the accumulation of several key gene alterations with associated genetic and epigenetic events. Although malignant mesothelioma (MM) has been demonstrated to be clearly correlated with asbestos exposure, it remains poorly understood how asbestos fibers confer key gene alterations and induce cellular transformation in normal mesothelial cells, which results in the acquisition of malignant phenotypes, including deregulated cell proliferation and invasion. Malignant mesothelioma presents with the frequent inactivation of tumor suppressor genes of p16(INK4a)/p14(ARF) on chromosome 9p21 and neurofibromatosis type 2 (NF2) on chromosome 22q12, with the latter being responsible for the NF2 familial cancer syndrome. In contrast, MM shows infrequent mutation of the p53 gene, which is one of the most frequently mutated tumor suppressor genes in human malignancies. Genetic abnormalities of oncogenes have also been studied in MM, but no frequent mutations have been identified, including the epidermal growth factor receptor (EGFR) and K-RAS genes. Recent studies have suggested the activation of other receptor tyrosine kinases, including Met, and the deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, although the alterations responsible for their activation are still not clear. Thus, further genome-wide studies of genetic and epigenetic alterations as well as detailed analyses of deregulated signaling cascades in MM are necessary to determine the molecular mechanisms of MM, which would also provide some clues for establishing a new molecular target therapy for MM.
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PMID:Molecular biology of malignant mesothelioma. 1956 83

Evidence points towards a pivotal role for cyclooxygenase (COX)-2 in promoting colorectal tumorigenesis through increasing prostaglandin E(2) (PGE(2)) levels. PGE(2) signalling is closely associated with the survival, proliferation and invasion of colorectal cancer cells. Recently, a reduction in PGE(2) inactivation, a process mediated by the nicotinamide adenine dinucleotide (NAD+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), has also been shown to promote tumoral PGE(2) accumulation. The hepatocyte growth factor (HGF) receptor, Met, is frequently over-expressed in colorectal tumours and promotes cancer growth, metastasis and resistance to therapy, although the mechanisms for this have not been fully elucidated. Here, we report that HGF/Met signalling can promote PGE(2) biogenesis in colorectal cancer cells via COX-2 up-regulation and 15-PGDH down-regulation at the protein and messenger RNA level. Pharmacological inhibition of MEK and PI3K suggested that both extracellular signal-regulated kinase (ERK) and AKT signalling are required for COX-2 protein up-regulation and 15-PGDH down-regulation downstream of Met. Notably, inhibition of Met with the small molecule inhibitor SU11274 reduced COX-2 expression and increased 15-PGDH expression in high Met-expressing cells. We also show that hypoxia potentiated HGF-driven COX-2 expression and enhanced PGE(2) release. Furthermore, inhibition of COX-2 impeded the growth-promoting effects of HGF, suggesting that the COX-2/PGE(2) pathway is an important mediator of HGF/Met signalling. These data reveal a critical role for HGF/Met signalling in promoting PGE(2) biogenesis in colorectal cancer cells. Targeting the crosstalk between these two important pathways may be useful for therapeutic treatment of colorectal cancer.
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PMID:HGF/Met signalling promotes PGE(2) biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells. 1963 28

Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC(50) values for autophosphorylation inhibition ranging between 0.15 and 1.5muM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCgamma and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain.
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PMID:Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274. 1978 61

Malignant mesothelioma (MM) is a tumor with poor prognosis associated with asbestos exposure. While it remains to be clarified how asbestos fibers confer genetic/epigenetic alterations and induce cellular transformation in normal mesothelial cells, the understanding of key molecular mechanisms of MM cell development, proliferation, and invasion has progressed. MM shows frequent genetic inactivation of tumor suppressor genes of p16(INK4a)/p14(ARF) and neurofibromatosis type 2 (NF2) which encodes Merlin, and epigenetic inactivation of RASSF1A. However, no frequent mutations of well-known oncogenes such as K-RAS and PIK3CA have been identified. Activation of multiple receptor tyrosine kinases including the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades are frequently observed in most MM cells. The tumor suppressive function of Merlin in MM cells is also being investigated by dissecting its possible downstream signaling cascade called the Hippo pathway. Further comprehensive delineation of dysregulated signaling cascades in MM cells will lead to identification of key addiction pathways for cell survival and proliferation of MM cells, which strongly promote establishment of a new molecular target therapy for MM.
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PMID:Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. 1979 48

Rhabdomyosarcoma is a highly metastatic tumor, mostly observed in children and adolescence. When diagnosed at early stages it is mostly curable. However, in advanced or metastatic stages the 5-years survival rate is below 20%. Thus, new treatment strategies for this tumor are needed. In this paper we showed that HSP90 inhibitors, geldanamycin and its analogs, can profoundly affect proliferation of rhabdomyosarcoma cells. We also showed that blocking of HSP90 function induces apoptosis of tumor cells and downregulates expression of anti apoptotic protein AKT. Cells exposed to geldanamycin and its analogs exhibit strong reduction of MET receptor expression and subsequent inhibition of HGF-dependent tumor cells migration and invasion. Interestingly, at concentrations sufficient to block tumor cells growth and motility, the 17AEP-GA, 17AAG and 17DMAP-GA were not toxic or only slightly toxic toward normal hematopoietic, mesenchymal and endothelial cells. This could be due to low HSP90 expression both at mRNA and protein level in these cells. Collectively, our findings suggest that blocking HSP90 action through geldanmycins could be in the future a part of new therapeutic strategies in rhabdomyosarcoma treatment.
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PMID:High anti tumor activity against rhabdomyosarcoma cells and low normal cells cytotoxicity of heat shock protein 90 inhibitors, with special emphasis on 17-[2-(pyrrolidin-1-yl)ethyl]-aminno-17-demethoxygeldanamycin. 1982 95

The development of the mammary gland requires an integrated response to specific growth factors and steroid hormones. Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, MET, are expressed and temporally regulated during mammary development and differentiation. Epidermal growth factor receptor (EGFR) and its ligands have also been implicated in mammary gland growth and morphogenesis. Since both cytokines seem to exert a morphogenic program in this tissue, we have investigated the possible concerted action of EGF and HGF on the HC11 cell line, a widely used model of nontumorigenic mammary cells. Western blot analysis indicated that HC11 expressed MET and EGFR, and showed ERK1/2 and AKT activation following HGF or EGF treatment. Analysis by real-time PCR and western blot showed that after an EGF but not HGF or insulin-like growth factor-I treatment, HC11 mammary cells exhibited an increase in MET expression at both the mRNA and protein levels, which was dependent on the AKT pathway. Simultaneous treatment with HGF and EGF increased proliferation, scatter, and invasion as assessed by cell count, cell cycle, scatter, and transwell assays. AKT inhibition did not influence the cooperation on proliferation or invasion after HGF+EGF treatment, while ERK1/2 inhibition abolished MET/EGFR cooperation on proliferation. HGF+EGF treatment increased the duration of ERK1/2 and AKT activation compared to HGF or EGF alone. All these data indicate that a crosstalk between the EGF and HGF pathways in mammary epithelial cells may modulate the development of the mammary gland.
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PMID:Epidermal growth factor and hepatocyte growth factor cooperate to enhance cell proliferation, scatter, and invasion in murine mammary epithelial cells. 1985 Jun 46

Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs frequently deregulated in human malignancies. We now report that miR-221&222 are overexpressed in aggressive non-small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation through the c-Jun transcription factor.
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PMID:miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. 1996 68

MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.
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PMID:Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. 2012 49

The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. Here, we describe MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met. MK-2461 inhibited in vitro phosphorylation of a peptide substrate recognized by wild-type or oncogenic c-Met kinases (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) with IC(50) values of 0.4 to 2.5 nmol/L. In contrast, MK-2461 was several hundredfold less potent as an inhibitor of c-Met autophosphorylation at the kinase activation loop. In tumor cells, MK-2461 effectively suppressed constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, and its downstream signaling to the phosphoinositide 3-kinase-AKT and Ras-extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. BIAcore studies indicated 6-fold tighter binding to c-Met when it was phosphorylated, suggesting that MK-2461 binds preferentially to activated c-Met. MK-2461 displayed significant inhibitory activities against fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor, and other receptor tyrosine kinases. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-Met-dependent mitogenesis, migration, cell scatter, and tubulogenesis. Seven of 10 MK-2461-sensitive tumor cell lines identified from a large panel harbored genomic amplification of MET or FGFR2. In a murine xenograft model of c-Met-dependent gastric cancer, a well-tolerated oral regimen of MK-2461 administered at 100 mg/kg twice daily effectively suppressed c-Met signaling and tumor growth. Similarly, MK-2461 inhibited the growth of tumors formed by s.c. injection of mouse NIH-3T3 cells expressing oncogenic c-Met mutants. Taken together, our findings support further preclinical development of MK-2461 for cancer therapy.
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PMID:MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. 2014 45

Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. (c)2010 AACR.
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PMID:CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. 2038 7


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