Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandin E(2) (PGE(2)) receptor subtype EP(2), which is coupled to cAMP metabolism, is known to mediate proliferation of primary human keratinocytes in vitro. The effect of gain or loss of EP(2) receptors in immortalized human keratinocytes (HaCat cells) was examined. HaCat keratinocytes were transfected with sense or anti-sense constructs of the EP(2) receptor. Loss or gain of EP(2) expression was documented by immunoblot and associated changes in agonist-stimulated cAMP production. Loss or gain of EP(2) receptor expression correlated with alterations in plating efficiencies but with modest affects on growth. When cell lines were studied in an organ culture model, anti-sense clones were highly invasive compared with vector controls and sense transfectants. A marked increase in prostaglandin production is commonly seen in malignant lesions. Because prostaglandin receptors are known to undergo ligand-induced receptor down-regulation, we sought to determine whether EP(2) receptor down-regulation results in increased invasiveness. In vector controls, invasiveness was reproduced by ligand-dependent EP(2) receptor down-regulation as assessed by immunohistochemistry. In addition, loss of EP(2) receptor expression was associated with decreased paxillin expression, a critical component of focal adhesion assembly. Thus, down-regulation of EP(2) receptors represents a potential mechanism for neoplastic progression to an invasive phenotype.
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PMID:Loss of the EP2 prostaglandin E2 receptor in immortalized human keratinocytes results in increased invasiveness and decreased paxillin expression. 1246 23

Studies on signal transduction pathways have generated various promising molecular targets for therapeutic inhibition in cancer therapy. Receptor tyrosine kinases represent an important class of such therapeutic targets. c-Met is a receptor tyrosine kinase that has been shown to be overexpressed and/or mutated in a variety of malignancies. A number of c-Met activating mutations, many of which are located in the tyrosine kinase domain, have been detected in various solid tumors and have been implicated in invasion and metastasis of tumor cells. It is known that stimulation of c-Met via its natural ligand, hepatocyte growth factor (also known as scatter factor, HGF/SF) results in a plethora of biological and biochemical effects in the cell. Activation of c-Met signaling can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. In this review, the role of c-Met dysregulation in tumor progression and metastasis is discussed in detail with particular emphasis on c-Met mutations. Moreover, we summarize current knowledge on various pathways of c-Met signal transduction, highlighting the central role in the cytoskeletal functions. In this summary is included recent data in our laboratory indicating that phosphorylation of focal adhesion proteins, such as paxillin, p125FAK, and PYK2, occurs in response to c-Met stimulation in lung cancer cells. Most importantly, current data on c-Met suggest that when mutated or overexpressed in malignant cells, c-Met would serve as an important therapeutic target.
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PMID:c-Met: structure, functions and potential for therapeutic inhibition. 1288 8

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.
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PMID:Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. 1614 58

Epithelial-mesenchymal transformation (EMT) and the resulting induction of cell motility are essential components of tissue remodeling during embryonic development and wound repair, as well as tumor progression to an invasive metastatic phenotype. Paxillin, a multi-domain adaptor and phosphoprotein has previously been implicated in integrin signaling and cell motility. In this report we characterize a novel paxillin gene product, paxillin delta, generated from an evolutionarily conserved internal translation initiation site within the full-length paxillin mRNA. Paxillin delta, which lacks the key phosphorylation sites Y31 and Y118 as well as the ILK and actopaxin binding LD1 motif, exhibits a restricted distribution to epithelial cell types and is downregulated during TGF-beta1-induced EMT of normal murine mammary gland (NMuMG) epithelial cells. Interestingly, Hic-5, a paxillin superfamily member, exhibits a reciprocal protein expression profile to paxillin delta. In addition, paxillin delta expression is maintained following NMuMG differentiation in a 3D collagen I gel while other focal adhesion components are downregulated. Paxillin delta protein expression coincided with reduced paxillin tyrosine phosphorylation in NMuMG cells and paxillin delta overexpression in CHO.K1 cells inhibited adhesion-mediated tyrosine phosphorylation of paxillin. Forced expression of paxillin delta in NMuMG cells suppressed cell migration whereas Hic-5 overexpression stimulated motility. Together our data support a role for paxillin delta as a naturally occurring functional antagonist of paxillin signaling potentially through suppression of a Crk-mediated pathway during processes associated with cell migration.
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PMID:Regulation of paxillin family members during epithelial-mesenchymal transformation: a putative role for paxillin delta. 1621 91

Src kinase plays a central role in growth factor signalling, regulating a diverse array of cellular functions including proliferation, migration and invasion. Recent studies have demonstrated that Src activity is frequently elevated in human tumours and correlates with disease stage. We have previously demonstrated that, upon acquisition of tamoxifen resistance, MCF7 cells display increased epidermal growth factor receptor (EGFR) activation and a more aggressive phenotype in vitro. Since tumours exhibiting elevated EGFR signalling may possess elevated levels of Src activity, we wished to investigate the role of Src in our MCF7 model of endocrine resistance. Src kinase activity was significantly elevated in tamoxifen-resistant (TamR) cells in comparison to wild type MCF7 cells. This increase was not due to elevated Src protein or gene expression. Treatment of TamR cells with the novel Src inhibitor, AZD0530, significantly reduced the amount of activated Src detectable in both cell types whilst having no effect on total Src levels. AZD0530 significantly suppressed the motile and invasive nature of TamR cells in vitro, reduced basal levels of activated focal adhesion kinase (FAK) and paxillin and promoted elongation of focal adhesions. Furthermore, the use of this compound in conjunction with the EGFR inhibitor, gefitinib, was markedly additive towards inhibition of TamR cell motility and invasion. These observations suggest that Src plays a pivotal role in mediating the motile and invasive phenotype observed in endocrine-resistant breast cancer cells. The use of Src inhibitors in conjunction with EGFR inhibitors such as gefitinib may provide an effective method with which to prevent cancer progression and metastasis.
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PMID:Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. 1633 27

Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex. The FAK-Src complex binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. In normal cells, multiple integrin-regulated linkages exist to activate FAK or Src. Activated FAK-Src functions to promote cell motility, cell cycle progression and cell survival. Recent studies have found that the FAK-Src complex is activated in many tumor cells and generates signals leading to tumor growth and metastasis. As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression.
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PMID:Integrin-regulated FAK-Src signaling in normal and cancer cells. 1691 35

Although ample evidence point to the central involvement of protease activated receptor-1 (PAR1) in tumor progression, little is known about the fate of the tumor when hPar1 is being silenced. We observed that hPar1 antisense clones exhibit low PAR1 levels, attenuated cell proliferation and invasion in vitro, and tumor formation in vivo. These clones showed noticeably reduced paxillin phosphorylation compared with the parental A375SM cells, whereas no change in the integrin levels was noticed. Antisense clones injected into the mice resulted in very few and only occasional small tumors, whereas advanced and vascularized tumors were observed in A375SM cells. The antisense-derived tumor sections expressed active caspase-3, increased terminal deoxynucleotidyl transferase-mediated nick-end labeling staining, and a markedly reduced proliferating cell nuclear antigen level compared with A375SM cell-derived tissue sections. Likewise, ablation of the hPar1 gene in a tetracycline-inducible hPar1 system leads to apoptosis in immature blood vessels, whereas mature vessels were unaffected. The activation of PAR1-induced pAkt/protein kinase B abrogated serum-deprived Bim(EL) induction and also markedly inhibited Bax levels. On the other hand, small interfering RNA silencing of the hPar1 gene induced the expression of Bim(EL), a direct substrate of Akt/protein kinase B and also induced expression of active caspase-9 and caspase-3. These results altogether identify PAR1 as a survival factor that protects cells from undergoing apoptosis. We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation.
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PMID:Protease-activated receptor-1 (hPar1), a survival factor eliciting tumor progression. 1737 29

Increased src tyrosine kinase expression and activity has been associated with colon cancer cell invasion and survival. Several signaling pathways are involved in the oncogenic activation of src during the adenoma to carcinoma progression and cellular invasion. In the present study, the synthetic ether lipid analog ET-18-OMe was shown to promote invasion of HCT-8/S11 colon cancer cells into collagen type I through the concomitant activation of src by phosphorylation at Tyr416 (5-30 min) in alpha1-integrin immunoprecipitates containing the integrin binding proteins talin and paxillin, as well as the phoshorylated and activated forms of focal adhesion kinase (FAK) at Tyr397 (a FAK kinase activation signal), Tyr576 and Tyr861. This was associated with the lateral redistribution of alpha1-integrins in focal aggregates and persistent activation of the p130Cas/JNK pathways at 5-30 min, with the subsequent induction and activation of the matrix metalloproteinases MMP-2 and MMP-9 (2-12 h). These activated molecular scaffolds and signaling cascades were not observed in immunoprecipitates of alpha2- and beta1-integrins, and tetraspanin CD9, an invasion and metastasis suppressor linked to integrins and FAK signaling. Our data demonstrate that the lateral redistribution and clustering of alpha1-integrins results in the recruitment of the FAK/src motility-promoting signaling complex involved in cancer cell invasion. Disruption of this proinvasive pathway was accomplished by the dominant negative mutant of src (K295R, kinase dead), src pharmacological inhibitor (PP1) and alpha1-integrin function blocking antibodies. These findings support the notion that the alpha1-integrin- and src-dependent signalosome is a relevant therapeutic target against tumor progression in colon cancer patients.
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PMID:Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by alpha1-integrins during colon cancer cell invasion. 1798 77

The scavenger receptor low-density lipoprotein receptor-related protein 1 (LRP-1) mediates the clearance of a variety of biological molecules from the pericellular environment, including proteinases which degrade the extracellular matrix in cancer progression. However, its accurate functions remain poorly explored and highly controversial. Here we show that LRP-1 silencing by RNA interference results in a drastic inhibition of cell invasion despite a strong stimulation of pericellular matrix metalloproteinase 2 and urokinase-type plasminogen activator proteolytic activities. Cell migration in both two and three dimensions is decreased by LRP-1 silencing. LRP-1-silenced carcinoma cells, which are characterized by major cytoskeleton rearrangements, display atypical overspread morphology with a lack of membrane extensions. LRP-1 silencing accelerates cell attachment, inhibits cell-substrate deadhesion, and induces the accumulation, at the cell periphery, of abundant talin-containing focal adhesion complexes deprived of FAK and paxillin. We conclude that in addition to its role in ligand binding and endocytosis, LRP-1 regulates cytoskeletal organization and adhesive complex turnover in malignant cells by modulating the focal complex composition, thereby promoting invasion.
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PMID:LRP-1 silencing prevents malignant cell invasion despite increased pericellular proteolytic activities. 1831 5

The cellular function and the role of matriptase-2 in cancer progression are poorly understood. This study assesses the importance of this protease in prostate cancer cell lines. Two prostate cancer cell lines, PC-3 and DU-145, previously displaying minimal expression of matriptase-2, were forced to over-express matriptase-2 using a human mammalian expression construct. Over-expression of matriptase-2 significantly reduced the invasive capacity and significantly slowed the migration rates of PC-3 and DU-145 cells in vitro. Similarly, PC-3 cells containing the matriptase-2 expression plasmid were dramatically less able to survive, grow and develop into noticeable tumours, compared to control PC-3 cells containing an empty plasmid alone, following subcutaneous inoculation into CD1 nude mice. This trend was observed throughout the experiment, becoming apparent after the initial reading on day 7 (P = 0.0002) and continuing to the experimental end point at day 27 (P = 0.0002). Enhanced matriptase-2 levels were also seen to correlate with increased fluorescent staining of the paxillin and FAK adhesion molecules, where a greater extent of these molecules were localised to the focal adhesion complexes. This data suggests a suppressive role for matriptase-2 in the invasion and migration of prostate cancer cells in vitro and also in their development and growth in vivo, highlighting the potential of this molecule to interfere with key stages of metastasis. Furthermore, the data presented implies a possible connection between matriptase-2 and the paxillin and FAK adhesion molecules which may ultimately contribute to the reduced migration rates seen in this study.
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PMID:Genetic upregulation of matriptase-2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation. 1844 7


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