Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of cisplatin (CDDP) as a potential radiosensitizer in tumors is controversial. Reports about CDDP interaction with radiation range from high radiosensitization to a clear sub-additive effect. We examined the effect of the combination of different concentrations of CDDP with radiation in murine mammary adenocarcinoma (EMT-6) and human ovarian carcinoma (OV-1063) cell lines. CDDP was given in the dose range of 0.01-3.0 micrograms/ml and radiation in the dose range of 1-6 Gy. A methylene blue assay of cell density was used for the evaluation of cell survival and rate of proliferation in 96-microwell plates. The validity of this assay for evaluation of cell survival was verified by colony-forming assay and radiolabeled thymidine uptake. The dose response to CDDP for both OV-1063 and EMT-6 cells lines was examined; the ID50 was 0.06 and 0.9 micrograms/ml respectively. A sub-additive effect of the combination of radiation with CDDP was clearly observed in the two cell lines tested; the increase in dose of each modality resulted in a decrease of the relative contribution on the effect of the other. These findings question the rationale of combining CDDP with radiation for the enhancement of tumor response, since with the increase in the dose of either modality the additional effect of the other decreases.
 ...
PMID:Sub-additive effect of the combination of radiation and cisplatin in cultured murine and human cell lines. 774 1

We investigated the role of integrin-fibronectin (FN) interactions in tumor cell adhesion. Two cloned tumor cell lines designated OV-LM (low-metastatic) and OV-HM (high-metastatic) were isolated from a murine ovarian carcinoma, OV2944. OV-LM and OV-HM cells exhibited high and low RGDS-sequence-dependent adhesiveness to FN, respectively. Both lines expressed comparable levels of alpha5 and alpha v integrins, which are capable of reacting with RGDS on FN. To compare the functions of these integrins between the two tumor lines, the signaling mechanism following FN stimulation was examined. Significant levels of phosphorylation of focal adhesion kinase (FAK) were detected in both OV-LM and OV-HM cells before FN stimulation. Whereas the level of FAK phosphorylation was appreciably enhanced in OV-LM cells stimulated with FN, stimulation of OV-HM cells with FN induced a reduction in the FAK phosphorylation in association with a significant decrease in the amount of FAK protein in the soluble compartment of cell lysates. A difference in the deposition of FN on the cell surface was also observed between the two types of tumor lines; OV-HM cells had an appreciably smaller amount of FN than OV-LM. Consistent with the functional abnormality of the integrin-FAK system and the smaller amount of FN on OV-HM, this clone exhibited a reduced cell-cell adhesion in the in vitro cell aggregation assay. Namely, OV-LM cells displayed a time-dependent increase in the formation of cell aggregates, whereas most OV-HM cells remained single. The formation of aggregates by OV-LM cells was inhibited by addition of RGDS peptide. These results indicate that the highly metastatic clone, OV-HM, exhibits a decreased capacity of cell-cell adhesion mediated by integrin-FN interactions and suggest that this defect is mainly due to the dysfunction of integrins/FAK rather than a decrease in the amount of integrins expressed on tumor cells.
 ...
PMID:A defect in cell-to-cell adhesion via integrin-fibronectin interactions in a highly metastatic tumor cell line. 904 98

Responses to the combination of cisplatin (CDDP) and radiation in experimental and clinical studies have been reported to vary from high radiosensitization to clear sub-additivity. We examined the combined effect of CDDP with ionizing radiation in both murine mammary adenocarcinoma (EMT-6) and human ovarian carcinoma (OV-1063) cells with special reference to the duration of CDDP exposure and timing of irradiation. Cell survival was measured with a colorimetric assay of cell density. The nature of interaction of cisplatin and radiation was evaluated using isobolograms and a combination index (CI). Exposure of both cell lines to CDDP for 24 hr before irradiation yielded an additive or slightly sub-additive response only if the exposure was extended for a few more hours after irradiation. In EMT-6 cells, the combination of radiation with subsequent continuous as well as short-term (4 to 6 hr) CDDP treatment was found to have a clear sub-additive effect; dose escalation of each modality reduced the additional effect of the other. The sub-additive effect may be explained by a radiation-induced arrest of cells in late S phase, which was dose- and time-dependent. Post-radiation exposure to CDDP further increased the S-phase arrest. In contrast, a 2 hr post-radiation drug exposure resulted in a supra-additive combined effect. Our results stress the crucial role of the timing and the doses of both modalities as well as the duration of post-radiation drug exposure on their combined effect.
 ...
PMID:Combination of cisplatin and radiation in cell culture: effect of duration of exposure to drug and timing of irradiation. 946 68

The importance of three-dimensional interactions between receptors with their respective ligands has been extensively explored during the binding process, but considerably less so for postbinding events such as induction of signaling pathways. Tumor cell receptor association with basement membrane proteins is believed to facilitate the metastatic process. Melanoma and ovarian carcinoma cells have been shown to utilize the alpha3beta1 integrin to bind to models of the alpha1(IV)531-543 sequence from basement membrane (type IV) collagen [Miles, A. J., et al. (1994) J. Biol. Chem. 269, 30939-30945; Miles, A. J., et al. (1995) J. Biol. Chem. 270, 29047-29050]. In the present study, the effects of ligand three-dimensional structure on possible signal transduction pathways induced by alpha3beta1 integrin binding have been evaluated. Human melanoma cell binding to type IV collagen resulted in Tyr phosphorylation of p125(FAK), consistent with prior studies correlating beta1 integrin subunit binding to collagen and p125(FAK) Tyr phosphorylation. Cross-linking of an anti-alpha3 integrin subunit monoclonal antibody also induced p125(FAK) Tyr phosphorylation. Incubation of melanoma cells with single-stranded or triple-helical peptide models of alpha1(IV)531-543 induced Tyr phosphorylation of intracellular proteins. Immunoprecipitation analysis identified one of these proteins as pp125(FAK). Induction of p125(FAK) Tyr phosphorylation was enhanced and the time of induction was shortened when the ligand was used in triple-helical conformation. Subsequent clustering of either the single-stranded or the triple-helical ligand also increased the level of p125(FAK) phosphorylation compared to unclustered ligand. The clustered triple-helical peptide ligand induced more rapid paxillin Tyr phosphorylation than the single-stranded ligand. In addition, the induction of activated proteases was found to be more rapid due to ligand triple helicity. Overall, these studies have shown that (i) a model of an isolated sequence from type IV collagen, alpha1(IV)531-543, can induce alpha3beta1 integrin-mediated signal transduction in melanoma cells and (ii) ligand conformation (secondary, tertiary, and/or quaternary structure) can directly influence several alpha3beta1 integrin-mediated signal transduction events. The effects of ligand conformation suggest that a "collagen structural modulation" mechanism may exist for tumor cell invasion, whereby triple-helical collagen promotes cell binding and induction of signal transduction, subsequently leading to collagen dissolution by proteases, decreased signal transduction, and enhanced tumor cell motility.
 ...
PMID:Effect of ligand conformation on melanoma cell alpha3beta1 integrin-mediated signal transduction events: implications for a collagen structural modulation mechanism of tumor cell invasion. 954 59

The alphavbeta3 integrin and its ligand vitronectin are expressed by differentiated epithelial ovarian carcinomas and carcinoma cell lines in culture. Moreover, alphavbeta3/vitronectin interaction influences adhesion and migration of ovarian carcinoma cells in culture. For a better understanding of the behavior of these carcinomas, it appeared necessary to study the characteristics of their normal counterpart, the ovarian surface epithelium (OSE). The present study showed that normal cultured human OSE cells, like the carcinoma cells, have the ability to synthesize vitronectin. The vitronectin receptor, alphavbeta3 integrin, is also expressed by OSE cells and is localized in focal contacts close to paxillin, a focal contact-specific protein, and p125(FAK), a cytoskeletal and signaling molecule. This localization suggested an active participation of the integrin in the adhesion and/or proliferation of OSE cells. Indeed, the use of a blocking antibody demonstrated that alphav integrins promote OSE cell adhesion on vitronectin but not on fibronectin and that these integrins are required for maximal proliferative activity. The results suggest a role of the alphavbeta3/vitronectin system in normal OSE physiology and demonstrate that the expression of this system by well-differentiated ovarian carcinomas reflects the retention of normal cell properties.
 ...
PMID:alphavbeta3 and vitronectin expression by normal ovarian surface epithelial cells: role in cell adhesion and cell proliferation. 1052 82

It is shown that adherent and non-adherent human ovarian carcinoma cells (OVP 10) secrete MMPs and their production was stimulated by fibronectin as documented by gelatinise zymography. These cells also presented an increase of ERK phosphorylating activity following fibronectin stimulation, regardless of their adhesion. Contrary to OVP 10 cells, the human urothelial cells (HCV-29) are more anchorage-dependent. They only secreted the MMPs under adherent conditions and they revealed a lower level of basal and fibronectin stimulated ERK phosphorylation activity. In addition, non-adhering HCV-29 cells showed post translational down-regulation of focal adhesion kinase.
 ...
PMID:Signal transduction in adherent and non-adherent human cell lines after fibronectin stimulation. 1060 93

The loss of mismatch repair enzymes increases the mutation rate in microsatellites and coding regions of the genome and appears to be involved in drug resistance. The replication error (RER+) phenotype, associated with microsatellite instability, has been widely described for both familial and sporadic colon cancers and for gastric and endometrial tumors. For ovarian cancer, the incidence of RER+ cases among sporadic tumors is still uncertain. We analyzed epithelial ovarian tumors and ovarian carcinoma cell lines for microsatellite instability and for mutations in the coding regions of different genes, including the recently discovered human CHK-1 gene, which has an important role in controlling cell cycle progression and whose coding region contains a poly(A)9 tract. Microsatellite instability and frameshift mutations in coding regions of BAX, TGFbetaRII, IGFIIR, E2F-4, ICE, and CHK-1 genes were analyzed in ovarian cancer samples and cell lines by polymerase chain reaction (PCR). Approximately 26% of patients showed microsatellite instability in two or more loci. BAT-26 locus showed no alteration in primary tumors. We detected a BAX mutation in one tumor sample and a TGFbetaRII mutation in one cell line. Our findings confirm the presence of the RER+ phenotype in sporadic ovarian cancer. The low rate of mutation in genes previously reported to be altered in colon and gastric cancer suggests that other not yet identified genes might be altered and could play a role in tumor progression and response to treatment in RER+ ovarian tumors.
 ...
PMID:Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer. 1075 43

Recently, an activating mutation of the SRC gene has been implicated in about one-tenth of advanced colon cancers. The SRC 531 mutation results in truncation of SRC directly C-terminal to the regulatory Tyr 530 and appears to activate the Tyr 530. To investigate whether mutation of SRC plays an important role in the development and progression of gynecological tumors, we performed mutational analysis of the entire coding region of SRC in 70 ovarian carcinomas, 68 endometrial carcinomas and 3 endometrial stromal sarcomas by means of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by nucleotide sequencing and restriction fragment length polymorphism (RFLP) analysis. We found one truncated mutation at codon 531 (Gln to Stop) in an endometrial carcinoma. However, we found no mutation of this gene in ovarian carcinoma or endometrial stromal sarcoma. Our results suggest that mutation of SRC may be implicated in a small proportion of endometrial carcinomas.
 ...
PMID:Mutation of the SRC gene in endometrial carcinoma. 1080 87

Cisplatin-induced apoptosis in epithelial ovarian cancer cells is in part a consequence of suppressed Xiap expression and upregulation of the Fas/FasL system. Changes in the expression of these 'cell death' and 'cell survival' genes lead to activation of caspase-3, and cleavage of MDM2 and FAK. Failure of cancer cells to maintain a balance in the expression of these genes in favor of apoptotic cell death may be an important factor of chemoresistance. Xiap may be a novel target for gene therapy of human ovarian epithelial cancer and, dependent on P53 status, expression of Xiap antisense alone or in combination with wild-type P53 sense may offer a new approach for the treatment of the chemoresistant cancer.
 ...
PMID:Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant? 1081 Feb 7

Two analogs of the peptide mimicking the 1977-1991 C- terminal part of fibronectin have been synthesized and tested. AWLI simulated human fibronectin fragment 1977-1991, whereas AWLII hybridized to both RGD and 1977-1991 fragments. AWLI and AWLII peptides inhibited the migration of the ovarian carcinoma cell line OVP10 regardless of the presence RGD. AWLI peptide inhibited spontaneous and fibronectin-activated cell migration and ERK1/2 activity. Neither AWLI nor fibronectin induced changes in FAK proteins, as could be judged from Western blots. In conclusion, it seems that the C-terminal fragment of fibronectin inhibits ERK1/2-dependent (random) migration of ovarian carcinoma cells.
 ...
PMID:Peptide analog of fibronectin that inhibits cell migration and ERK 1/2 activity. 1178 76


1 2 3 4 5 6 7 8 9 10 Next >>