Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ABL 364 is a murine monoclonal IgG3 antibody directed against the Lewis Y carbohydrate antigen (Le(y)) expressed on the surface of many epithelial cell tumors. The antibody mediates cytotoxicity via activation of human complement or human effector cells, and has been evaluated in several clinical trials including two Phase I/II trials in relapsed small cell lung cancer and metastatic breast cancer. To improve the effector functions of the antibody, increase its half-life in circulation, and avoid the human antimouse antibody response, two chimeric and several humanized antibodies were constructed for evaluation. The chimeric IgG1 is more potent than the murine IgG3 in tumor cell lysis via activation of human peripheral mononuclear cells (10-fold), but somewhat less effective in complement-dependent lysis (2-3 fold). The chimeric IgG3 is slightly less potent than the IgG1. A humanized IgG1 was constructed by combining the complementarity-determining regions of the ABL 364 antibody with human framework and constant regions. Several additional variants were subsequently constructed to improve the binding affinity and increase expression of the antibody. Two of the variants, designated I and K, differ by a single amino acid at position 75 of the heavy chain. Both variants have affinity within 2-fold of the chimeric IgG1 antibody and retain the cytolytic activities toward tumor cell lines. However, it was possible to express variant K at a significantly higher level (5- 10-fold) than variant I. Pharmacokinetics of the humanized ABL 364 antibody variant K was compared with that of the parent murine antibody in rhesus monkeys. It was shown that the terminal half-life of the humanized antibody in rhesus monkeys is 14-20 days, with a mean of 16.3 days, while that of the parent murine antibody is only 1.9 days.
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PMID:Humanized anti-Lewis Y antibodies: in vitro properties and pharmacokinetics in rhesus monkeys. 864 Jul 70

Small cell lung cancer (SCLC) cell growth is sustained by multiple autocrine and paracrine growth loops involving neuropeptides. The bombesin family of peptides are autocrine growth factors in H345 SCLC cells and provide a paradigm for the study of growth factors and mitogenic signaling in SCLC cells. We show that bombesin (and other neuropeptides) stimulates protein tyrosine phosphorylation (particularly focal adhesion kinase) and protein tyrosine kinase (PTK) activity in intact SCLC cells. Furthermore, the broad spectrum neuropeptide receptor antagonist [D-Arg, D = Phe, D-Trp, Leu11]substance P inhibits all neuropeptide-mediated signals (including PTK activation), SCLC cell growth in vivo and in vitro, and also increases the natural rate of apoptosis seen in growing SCLC cell lines. Hence the effect of selective PTK inhibition on SCLC cell growth and apoptosis was examined. We show that selective inhibition of PTK activity, with genistein and (3,4,5-tri-hydroxyphenyl)-methylene(-propanedinitrile) tyrphostin-25 inhibits basal and neuropeptide-stimulated SCLC cell growth. Genistein and tyrphostin-25 also stimulate apoptosis in SCLC cells. Inhibition of proliferation in these cells is intimately linke to apoptosis, because these changes occurred without any effect on SCLC cell cycle kinetics, suggesting that apoptosis occurs independently of the cell cycle and that failure to progress through the cell cycle results in apoptosis. Because tyrphostin-25 fails to influence p53 or Bcl-2 expression in these cells, this mode of programmed cell death appears to be via a p53- and Bcl-2-independent mechanism. These results provide evidence that tyrosine phosphorylation is a mitogenic signal in SCLC cells and suggest that regulation of the level of protein tyrosine phosphorylation represents a critical determinant of whether SCLC cells survive and proliferate or die by apoptosis. Thus PTK inhibition may provide a novel therapeutic option in SCLC that has become resistant to conventional chemotherapeutic agents.
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PMID:Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells. 879 1

Stimulation of small cell lung cancer (SCLC) cells with neuropeptides bombesin, bradykinin, gastrin, and neurotensin resulted in increased tyrosine kinase activity and tyrosine phosphorylation of a number of polypeptides including a p120 kDa polypeptide identified by immunoblotting as focal adhesion kinase (p125FAK). The neuropeptides stimulated a rapid, concentration-dependent phosphorylation of p125FAK (EC50 of 1 nM, 5 nM, and 2 nM for bombesin, bradykinin, and gastrin, respectively), which was receptor mediated and inhibited by both specific and broad-spectrum neuropeptide receptor antagonists. Specific inhibition of protein tyrosine kinase activity by tyrphostin-25 inhibited both basal and neuropeptide-stimulated SCLC cell growth. These results identify a novel neuropeptide-stimulated growth signaling event in SCLC cells.
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PMID:Neuropeptides stimulate tyrosine phosphorylation and tyrosine kinase activity in small cell lung cancer cell lines. 880 78

Small cell lung cancer (SCLC) is characterized by early and widespread metastases. Anchorage-independent growth is pivotal to the ability of tumor cells to survive and metastasize in vivo and, under in vitro conditions, allows transformed cells to form colonies in semisolid medium. Here, we report that of five SCLC cell lines tested, all exhibited high basal constitutive phosphoinositide 3-kinase (PI 3-kinase) activity, which results in high basal protein kinase B (PKB) and ribosomal p70 S6 kinase activity (p70s6k). Inhibition of PI 3-kinase activity markedly inhibited SCLC cell proliferation in liquid culture as a result of stimulating apoptosis and promoting cell cycle delay in G1. Furthermore, PI 3-kinase inhibition reduced basal SCLC cell colony formation in agarose semisolid medium that could not be overcome by the addition of neuropeptide growth factors. Thus, constitutive PI 3-kinase activity in SCLC cells plays an important role in promoting the growth and anchorage independence of SCLC. This is not due to activating ras mutations or increased basal src or focal adhesion kinase activity. These data represent the first description of constitutively activated PI 3-kinase/PKB in any human cancer. Constitutive activation of these integrin-dependent signaling events provides a molecular explanation for the anchorage-independent growth of SCLC cells and may account for the nonadherent phenotype and highly metastatic nature of this aggressive cancer. Up-regulation of the PI 3-kinase/PKB pathway may, therefore, represent a novel target for therapeutic intervention in SCLC.
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PMID:The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway. 982 38

New efforts in cancer therapy are being focused at various levels of signaling pathways. With phosphoinositide 3-kinase (PI3-K) potentially being necessary for a range of cancer-related functions, we have investigated the influence of selected inositol tris- to hexakisphosphates on cell growth and tumorigenicity. We show that micromolar concentrations of inositol 1,3,4,5,6-pentakisphosphate and inositol 1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P(4)] inhibit IGF-1-induced [(3)H]-thymidine incorporation in human breast cancer (MCF-7) cells and the ability to grow in liquid medium and form colonies in agarose semisolid medium by small cell lung cancer (SCLC) cells, a human cancer cell line containing a constitutively active PI3-K. In an ovarian cancer cell line that also contains a constitutively active PI3-K (SKOV-3 cells), Ins(1,4,5,6)P(4) again inhibited liquid medium growth. Furthermore, when applied extracellularly, inositol 1,3,4,5-tetrakisphosphate was shown indeed to enter SCLC cells. These effects appeared specifically related to PH domains known to bind to phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P(2)] and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)], indicating involvement of the PI3-K downstream target protein kinase B (PKB/Akt). This was further supported by inhibition of PKB/Akt PH domain membrane targeting in COS-7 cells by Ins(1,4,5,6)P(4). Thus, we propose that specific inositol polyphosphates inhibit PI3-K by competing with PtdIns(3,4, 5)P(3)-binding PH domains and that this occurs mainly at the level of the downstream PI3-K target, PKB/Akt.
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PMID:Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines. 1083 40

The effects of cholecystokinin (CCK) antagonists on small cell lung cancer (SCLC) cells were investigated. CI-988, L-365,260, and L-364,718 inhibited specific (125)I-CCK-8 binding to NCI-H209 cells with IC(50) values of 5, 2, and 200 nM. ([R-(R*,R*)]-4[[2-[[3-(1H-Indole-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1(3,7)]- dec-2-yloxy)carbonyl[amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid) (CI-988; 100 nM) inhibited the ability of 10 nM CCK-8 to elevate cytosolic Ca(2+) in 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'-methylphenoxy)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester-loaded NCI-H209 cells. By Western blot, CI-988 inhibited tyrosine phosphorylation of focal adhesion kinase and paxillin stimulated by CCK-8. Also, CI-988 inhibited tyrosine phosphorylation of mitogen-activated protein kinase stimulated by CCK-8. By Northern blot, CI-988 antagonized the ability of 10 nM CCK-8 to increase c-fos mRNA in NCI-H209 cells. Also, CI-988 inhibited the ability of CCK-8 to increase vascular endothelial cell growth factor mRNA. Using a [3-(4,5 dimethylthiazol-2-yl)-2.5-diphenyl-2H-tetrazolium bromide] and clonogenic assay, CI-988 inhibited the proliferation of NCI-H209 cells in vitro. Using nude mice, CI-988 inhibited the proliferation of NCI-H209 xenografts. These results suggest that CI-988 is a CCK(2) receptor antagonist that inhibits the proliferation of SCLC cells.
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PMID:CI-988 inhibits growth of small cell lung cancer cells. 1171 7

The c-Met receptor tyrosine kinase and its ligand HGF (hepatocyte growth factor) have been shown to be involved in angiogenesis, cellular motility, growth, invasion, and differentiation. The role of c-Met/HGF axis in small cell lung cancer (SCLC) has not been reported previously. We have determined the expression of p170(c-Met) precursor and p140(c-Met) beta-chain in seven SCLC cell lines by immunoblotting. We used the SCLC cell line H69, which expressed an abundant amount of c-Met to study the function and downstream effects of c-Met activation. Stimulation of H69 cells with HGF (40 ng/ml, 6-h stimulation) significantly altered cell motility of the SCLC cells with increased formation of filopodia and membrane ruffling, characterized as membrane blebbing, as well as increased migration of the cellular clusters were seen. We have further studied the signal transduction pathways of HGF/c-Met in the H69 cell line. The stimulation of H69 with HGF (40 ng/ml, >24 h, maximal at 1 h) increased the amount of reactive oxygen species formed by 34%. HGF stimulation (40 ng/ml, 7.5-min stimulation) of H69 cells showed increased tyrosine phosphorylated bands identified at M(r) 68,000, 120,000-140,000, and 200,000. Some of these tyrosine-phosphorylated bands were identified as the focal adhesion proteins paxillin, FAK, PYK2, and the c-Met receptor itself. Phospho-specific antibodies show that tyrosines at amino acid (a.a.) 31 of paxillin, and autophosphorylation sites at a.a. 397 of p125FAK, and a.a. 402 of PYK2 are phosphorylated in response to HGF/c-Met signaling. We also demonstrate that the Hsp90 inhibitor geldanamycin, which also affects c-Met, reduced the growth and viability of four of four SCLC cell lines by 25% to 85%, over a 72-h time period. Geldanamycin caused apoptosis of SCLC cells, as well as led to increased levels of Hsp70 but not Hsp90. These results demonstrate that c-Met/HGF pathway is functional in SCLC, and it would be useful to target this pathway toward novel therapy.
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PMID:Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. 1183 85

CD98, an early marker of T-cell activation, is an important regulator of integrin-mediated adhesion events. Previous studies suggest that CD98 is coupled to both cellular activation and transformation and is involved in the pathogenesis of viral infection, inflammatory disease, and cancer. Understanding of the molecular mechanisms underlying CD98 activity may have far-reaching practical applications in the development of novel therapeutic strategies in these disease states. Using small cell lung cancer cell lines, which are nonadherent, nonpolarized, and highly express CD98, we show that, in vitro, under physiological conditions, CD98 is constitutively associated with beta1 integrins regardless of activation status. Cross-linking CD98 with the monoclonal antibody 4F2 stimulated phosphatidylinositol (PI) 3-kinase, PI(3,4,5)P(3), and protein kinase B in the absence of integrin ligation or extracellular matrix engagement. Furthermore, cross-linking CD98 promoted anchorage-independent growth. Using fibroblasts derived from beta1 integrin null stem cells (GD25), wild-type GD25beta1, or GD25 cells expressing a mutation preventing beta1 integrin-dependent FAK phosphorylation, we demonstrate that a functional beta1 integrin is required for CD98 signaling. We propose that by cross-linking CD98, it acts as a "molecular facilitator" in the plasma membrane, clustering beta1 integrins to form high-density complexes. This results in integrin activation, integrin-like signaling, and anchorage-independent growth. Activation of PI 3-kinase may, in part, explain cellular transformation seen on overexpressing CD98. These results may provide a paradigm for events involved in such diverse processes as inflammation and viral-induced cell fusion.
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PMID:Cross-linking CD98 promotes integrin-like signaling and anchorage-independent growth. 1218 50

The effects of carboxyamido-triazole (CAI) on small cell lung cancer (SCLC) cells were investigated. Using SCLC cell lines NCI-H209 or H345, 20 micro M CAI had little effect on basal cytosolic Ca(2+) but inhibited the ability of 10 nM bombesin (BB) or 1 nM neurotensin (NT) to elevate cytosolic Ca(2+). Also, CAI, impaired the ability of BB or NT to cause tyrosine phosphorylation of focal adhesion kinase. In contrast, CAI did not affect the ability of (125I-Tyr(4))BB or 125I-NT to bind with high affinity to NCI-H345 cells. These results indicate that CAI impairs SCLC second messenger activation, but not neuropeptide receptor binding. Using a MTT growth assay, CAI inhibited the proliferation of NCI-H209 or H345 cells in a concentration-dependent manner with little proliferation occurring using 100 micro M CAI. Also, CAI inhibited colony formation of NCI-H209 or H345 cells in a dose-dependent manner in vitro. In vivo, CAI (2 mg/day by gavage) inhibited significantly NCI-H209 xenograft proliferation in nude mice. Animals treated daily with CAI had significantly reduced CD31 immunostaining of microvessels in the tumor. Also, CAI inhibited the increase in vascular endothelial cell growth factor (VEGF) mRNA after addition of BB to SCLC cells. These results suggest that CAI inhibits the growth of SCLC cells as well as the angiogenesis of SCLC tumors in a VEGF-dependent manner.
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PMID:CAI inhibits the growth of small cell lung cancer cells. 1260 66

Caveolin-1 (CAV1), an essential structural constituent of caveolae that plays an important role in cellular processes such as transport and signaling, has been implicated in the development of human cancers. However, it is unclear whether CAV1 is acting like an oncogene or tumor suppressor gene. We found that CAV1 expression was reduced or absent in 95% of small cell lung cancers (SCLCs; n = 21 lines), whereas it was retained in 76% of non-small cell lung cancers (NSCLCs; n = 25 lines) compared with normal human lung epithelial cultures, where it was abundantly expressed. CAV1 expression was tightly linked to the ability to grow attached to the plastic cell culture surface, whereas CAV1-nonexpressing lung cancers of both SCLC and NSCLC type grew as suspension cultures. In addition, attached lung cancer cultures expressed phosphorylated focal adhesion kinase, whereas suspension cultures did not. Lack of CAV1 expression was tightly associated with CAV1 promoter methylation (P < 0.0001) such that CAV1 methylation was found in 93% of SCLCs (n = 15) and 9% of NSCLCs (n = 11), whereas 5-aza-2'deoxycytidine treatment restored CAV1 expression in SCLCs. Exogenous CAV1 expression in SCLCs significantly inhibited soft-agar colony formation but did not lead to attachment. By contrast, CAV1 knockdown in NSCLCs mediated by small interfering RNA against CAV1 led to inhibition of cellular proliferation and soft-agar and liquid colony formation. Importantly, CAV1 knockdown led to reduced phospho-focal adhesion kinase and RalA, but not RalB, levels in NSCLC cells. These results suggest different roles for CAV1 in SCLC, where CAV1 acts like a tumor suppressor gene, and NSCLC, where it appears required for survival and growth.
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PMID:Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer. 1520 42


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