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)

Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G(1) arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G(1) arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors.
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PMID:Identification of c-Src as a potential therapeutic target for gastric cancer and of MET activation as a cause of resistance to c-Src inhibition. 2040 49

The RON receptor tyrosine kinase and its ligand macrophage stimulating protein (MSP) play a role in epithelial tumorigenesis. We report here a novel RON variant that antagonizes the RON-MSP pathway in various cancer cells. The variant is an 85 kDa soluble protein from an mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop codon leading to the formation of a RON variant consisting of the entire 35 kDa alpha-chain and a 45 kDa partial extracellular beta-chain. The protein was featured by a sema domain, a hinge motif and a portion of the first IPT unit (designated as RONDelta85). RONDelta85 binds directly to MSP, forms MSP-RONDelta85 complex, and inhibits RON phosphorylation. RONDelta85 disrupts RON or RONDelta160 dimerization, prevents their phosphorylation, and attenuates downstream signaling events. The action of RONDelta85 is specific to RON and has no effect on MET and EGFR. In colon and pancreatic cancer cells, RONDelta85 inhibits spontaneous or MSP-induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RONDelta85 also inhibits spontaneous and MSP-induced cell migration. We conclude that RONDelta85 is an antagonist to the MSP-RON pathway, which has potential for regulating RON/RON160-mediated tumorigenic activities.
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PMID:Inhibition of MSP-RON signaling pathway in cancer cells by a novel soluble form of RON comprising the entire sema sequence. 2042 80

Deregulated hepatocyte growth factor (HGF)/c-MET axis has been correlated with poor clinical outcome and drug resistance in many human cancers. Identification of novel regulatory mechanisms influencing HGF/c-MET signaling may therefore be necessary to develop more effective cancer therapies. In our study, we show that multiple human cancer tissues and cells express filamin A (FLNA), a large cytoskeletal actin-binding protein, and expression of c-MET is significantly reduced in human tumor cells deficient for FLNA. The FLNA-deficient tumor cells exhibited poor migrative and invasive ability in response to HGF. On the other hand, the anchorage-dependent and independent tumor cell proliferation was not altered by HGF. The FLNA-deficiency specifically attenuated the activation of the c-MET downstream signaling molecule AKT in response to HGF stimulation. Furthermore, FLNA enhanced c-MET promoter activity by its binding to SMAD2. The impact of FLNA deficiency on c-MET expression and HGF-mediated cell migration in human tumor cells was confirmed in primary mouse embryonic fibroblasts deficient for Flna. These data suggest that FLNA is one of the important regulators of c-MET signaling and HGF-induced tumor cell migration.
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PMID:Filamin a mediates HGF/c-MET signaling in tumor cell migration. 2047 7

Hepatocyte growth factor/c-MET has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we first investigated the role of c-Met in a large series of DLBCL tissues in a tissue microarray format. We then followed this with in vitro studies on DLBCL cell lines using either pharmacological inhibitors of c-Met or siRNA knockdown strategy. c-Met was found to be overexpressed in 73.2% of patients (186/254) and was significantly associated with overexpression of p-AKT (P=0.0274), p-GSK3 (P=0.0047) and Ki-67 (P=0.0012). Interestingly, c-Met overexpression was significantly more common in the germinal center subtype of DLBCL, as compared with activated B cell subtype (P=0.0002). Overexpression of c-Met in DLBCL was significantly associated with better survival (P=0.0028) and remained significant in multivariate analysis with international prognostic index, thereby confirming c-Met as independent prognostic marker for better outcome in DLBCL. In vitro pharmacological c-Met inhibition and siRNA targeted against c-Met triggered caspase-dependent apoptosis. These findings provide evidence that c-Met is an independent prognostic marker for better outcome in Middle Eastern DLBCL. This data also enlightens the fact that c-Met through AKT kinase has a critical role in carcinogenesis of DLBCL, and strongly suggest that targeting c-Met may have therapeutic value in treatment of DLBCL.
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PMID:Inhibition of c-MET is a potential therapeutic strategy for treatment of diffuse large B-cell lymphoma. 2053 Dec 93

Treatment outcomes in advanced or metastatic non-small-cell lung cancer (NSCLC) remain unsatisfactory, with low long-term survival rates. Palliative chemotherapy offers a median survival not exceeding 1 year. To date, various combinations of cytotoxic drugs have not improved treatment results beyond what has been observed with platinum doublets. By contrast, molecular targeted drugs may block important pathways that drive cancer progression and achieve long-term disease control. Conflicting results have demonstrated marginal benefit with EGFR inhibitors, anti-EGFR monoclonal antibodies and antiangiogenic strategies in unselected populations of patients with advanced NSCLC. However, patients with an EGFR mutation are likely to respond to agents that target this gene. Novel targeted therapies that interfere with insulin-like growth factor 1 receptor, or the EML4-ALK fusion protein have shown promising activity. Aberrations in other key signaling pathways and molecules, such as RAS/RAF/MEK, PI3K/AKT/mTOR, or MET kinase, have been identified as crucial targets, especially in resistant patients. Novel drugs aimed at these abnormalities are already in the clinic. This Review outlines the current state-of-the-art research for targeted therapy in NSCLC.
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PMID:Targeted therapy in non-small-cell lung cancer--is it becoming a reality? 2055 45

Overexpression of the RON receptor tyrosine kinase contributes to pathogenesis of epithelial cancers and disruption of RON signals has potential for therapeutic intervention. Here, we report the inhibitory effects of monoclonal antibodies (Zt/g4, Zt/f2 and Zt/c9) on RON expression and tumorigenic activities in colon cancer cells. Persistent treatment of colon SW620 or other cells with Zt/g4 dramatically down-regulated RON expression as evident by Western blot and cell surface fluorescent analyses. The effect was both concentration and time-dependent and specific to RON but not to structure-related MET or -unrelated EGFR. The cause of reduction was antibody-induced receptor internalization followed by protein degradation through lysosome and proteasome-mediated pathways. Down-regulation of RON impaired intracellular signaling events. Phosphorylation of Erk1/2 and AKT was dramatically reduced after Zt/g4 treatment. Zt/g4 treatment also affects activities of DVL and GSK-3beta, which results in diminished beta-catenin nuclear translocation. Functional studies revealed that Zt/g4 treatment changes cellular morphology and affects colony formation in soft agar. It also increased the sensitivity of SW620 cells in response to gemcitabine-induced cytotoxicity. In this case, the death of SW620 cells was significantly increased when Zt/g4 was used in combination with gemcitabine. We conclude that persistent treatment of cancer cells with antibodies specific to RON extracellular domains results in down-regulation of RON expression. The reduced RON expression is accompanied with impaired signaling events, diminished tumorigenic activities and enhanced sensitivity towards cytotoxic drugs. Thus, Zt/g4-directed targeting could have therapeutic implication for controlling tumorigenic phenotypes of cancer cells.
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PMID:Monoclonal antibody (mAb)-induced down-regulation of RON receptor tyrosine kinase diminishes tumorigenic activities of colon cancer cells. 2059 75

The pericarp of Sapindus mukorossi Gaertn is traditionally used as an expectorant in Japan, China, and Taiwan. Activated neutrophils produce high concentrations of the superoxide anion (O(2)(-)) and elastase known to be involved in airway mucus hypersecretion. In the present study, the anti-inflammatory functions of hederagenin 3-O-(3,4-O-di-acetyl-alpha-L-arabinopyranoside)-(1-->3)-alpha-l-rhamnopyranosyl-(1-->2)-alpha-l-arabinopyranoside (SMG-1), a saponin isolated from S. mukorossi, and its underlying mechanisms were investigated in human neutrophils. SMG-1 potently and concentration-dependently inhibited O(2)(*-) generation and elastase release in N-Formyl-Met-Leu-Phe (FMLP)-activated human neutrophils. Furthermore, SMG-1 reduced membrane-associated p47(phox) expression in FMLP-induced intact neutrophils, but did not alter subcellular NADPH oxidase activity in reconstituted systems. SMG-1 attenuated FMLP-induced increase of cytosolic calcium concentration and phosphorylation of p38 MAPK, ERK, JNK, and AKT. However, SMG-1 displayed no effect on cellular cAMP levels and activity of adenylate cyclase and phosphodiesterase. Significantly, receptor-binding analysis showed that SMG-1 inhibited FMLP binding to its receptor in a concentration-dependent manner. In contrast, neither phorbol myristate acetate-induced O(2)(*-) generation and MAPKs activation nor thapsigargin-caused calcium mobilization was altered by SMG-1. Taken together, our results demonstrate that SMG-1 is a natural inhibitor of the FMLP receptor, which may have the potential to be developed into a useful new therapeutic agent for treating neutrophilic inflammatory diseases.
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PMID:The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation. 2059 99

Invasion of eukaryotic target cells by pathogenic bacteria requires extensive remodelling of the membrane and actin cytoskeleton. Here we show that the remodelling process is regulated by the ubiquitin C-terminal hydrolase UCH-L1 that promotes the invasion of epithelial cells by Listeria monocytogenes and Salmonella enterica. Knockdown of UCH-L1 reduced the uptake of both bacteria, while expression of the catalytically active enzyme promoted efficient internalization in the UCH-L1-negative HeLa cell line. The entry of L. monocytogenes involves binding to the receptor tyrosine kinase Met, which leads to receptor phosphorylation and ubiquitination. UCH-L1 controls the early membrane-associated events of this triggering cascade since knockdown was associated with altered phosphorylation of the c-cbl docking site on Tyr1003, reduced ubiquitination of the receptor and altered activation of downstream ERK1/2- and AKT-dependent signalling in response to the natural ligand Hepatocyte Growth Factor (HGF). The regulation of cytoskeleton dynamics was further confirmed by the induction of actin stress fibres in HeLa expressing the active enzyme but not the catalytic mutant UCH-L1(C90S) . These findings highlight a previously unrecognized involvement of the ubiquitin cycle in bacterial entry. UCH-L1 is highly expressed in malignant cells that may therefore be particularly susceptible to invasion by bacteria-based drug delivery systems.
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PMID:The ubiquitin C-terminal hydrolase UCH-L1 promotes bacterial invasion by altering the dynamics of the actin cytoskeleton. 2060 41

Hepatocellular carcinoma (HCC) is a highly prevalent, treatment-resistant malignancy with a multifaceted molecular pathogenesis. Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective, because targeting them may help to reverse, delay or prevent tumorigenesis. In this review, we explore some of the major pathways implicated in HCC. These include the RAF/MEK/ERK pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, WNT/beta-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling. We focus on the role of these pathways in hepatocarcinogenesis, how they are altered, and the consequences of these abnormalities. In addition, we also review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against these pathways, with early evidence of success.
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PMID:The role of signaling pathways in the development and treatment of hepatocellular carcinoma. 2063 98

The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a variety of human malignancies. However, its role in epithelial ovarian carcinoma (EOC) has not been clearly elucidated. Therefore, we investigated the role of HGF/c-Met signaling pathway in a large series (156) of Saudi EOC patient samples, a panel of cell lines, and xenografts in a NUDE mouse model. Using immunohistochemistry, c-Met overexpression was found in 27.2% Middle Eastern EOC samples and was associated with an advanced tumor stage (P=0.0187). c-Met overexpression was also associated with antiapoptotic markers X-chromosome-linked inhibitors of apoptosis (XIAP) (P=0.0008) and Bcl-XL (P=0.0493) expression. Treatment of EOC cell lines with PHA665752 causes a dose-dependent inhibition of cell viability and induction of apoptosis. Furthermore, PHA665752 treatment causes dephosphorylation of AKT and downregulation of antiapoptotic proteins XIAP and Bcl-XL. In addition, PHA665752-induced apoptosis occurs through activation of Bax-mediated release of cytochrome c and activation of caspases. Finally, co-treatment of EOC with PHA665752 and cisplatin causes augmented effect on apoptosis of EOC cells and resulted in synergistic inhibition of EOC xenograft tumor growth in NUDE mice. These results indicate that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of EOC.
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PMID:HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma. 2066 Dec 29


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