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)

This study was undertaken to determine the effect of tumor size and tumor carcinoembryonic antigen (CEA) content on the uptake of indium 111 (111In)-labeled anti-CEA monoclonal antibody in nude mice bearing xenografts. The tumor cell lines were WiDr, SW403, and LS174T, human colon cancer derivatives. The murine breast carcinoma cell line EMT-6 was used as a control. Tumor CEA levels (ng/g of tumor +/- standard error of the mean [SEM], measured by enzyme immunoassay (EIA) were: EMT-6, 0; WiDr, 105 +/- 5.7; LS174T, 2052 +/- 198; SW403, 17,575 +/- 1,785. The 111In-labeled monoclonal antibody was injected intravenously into mice bearing a single tumor. At 48 hours postinjection, scintiscan was performed, and the mice were killed so that biodistribution studies could be performed. The uptake of the monoclonal antibody was expressed as percent injected counts per minute per gram of tissue +/- SEM. The non-CEA-producing tumor, EMT-6, showed the lowest tumor uptake (1.4 +/- 0.3). WiDr, an intermediate CEA-producing tumor, showed some tumor uptake (16.4 +/- 1.5). The high CEA-producing tumors, SW403 and LS174T, had high tumor uptake (29.5 +/- 5.0 and 51.1 +/- 6.1, respectively). Biodistribution and scintiscan quality were closely related. Although LS174T had the best tumor uptake, SW403 had the highest CEA tumor content, indicating tumor CEA content cannot entirely predict scintiscan and biodistribution results. Tumor-to-blood (T/B), tumor-to-liver (T/L), and liver-to-blood (L/B) ratios were calculated for each animal and compared with tumor size. It was found that T/L had a negative correlation with tumor size (r = -0.72) and L/B had a positive correlation with tumor size (r = 0.94). These ratios may be useful clinically to follow response to therapy.
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PMID:The effect of tumor CEA content and tumor size on tissue uptake of indium 111-labeled anti-CEA monoclonal antibody. 394 92

The bioreductive alkylating agent mitomycin C (mitomycin) has been shown to have greater activity under hypoxic than oxic conditions on murine cell lines such as the EMT-6 fibrosarcoma cell line. Solid tumors are known to contain hypoxic cells and are relatively resistant to ionizing radiation and some chemotherapeutic agents. We tested the cytotoxicity of mitomycin against fresh biopsies of human carcinomas under both hypoxic and oxic conditions in the human tumor clonogenic assay (HTCA). Additionally, we examined the metabolism of mitomycin by sonicates of the murine EMT-6 cells and the human WiDR colon carcinoma cells. We confirmed that under our clonogenic assay conditions the EMT-6 cell line was more sensitive to mitomycin under hypoxic than oxic conditions. Additionally, we established that EMT-6 cells also metabolize mitomycin at a more rapid rate under hypoxic than oxic conditions. However, these effects of hypoxia on mitomycin activity were not demonstrable for the human WiDR colon cancer cell line. In addition to these findings, the cytotoxicity of mitomycin was either unchanged or reduced under hypoxic conditions for ten fresh human tumors tested for mitomycin sensitivity in HTCA. Based on these observations, we conclude that the potentiating effect of hypoxia on mitomycin metabolism and biological activity may be peculiar to the murine EMT-6 and S-180 cell lines and that mitomycin C is not likely to have differential efficacy against hypoxic human carcinoma cells.
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PMID:Cytotoxicity of mitomycin C on clonogenic human carcinoma cells is not enhanced by hypoxia. 642 4

We have previously reported on the expression of interleukin-4 receptors (IL-4R) on many human epithelial cancer cells; however, the binding characteristics, structure, function, and signal transduction through the IL-4R in cancer cells is not known. IL-4 binding characteristics were determined in human colon carcinoma cell lines by a 125I-IL-4 binding assay, which demonstrated that the HT-29 and WiDr colon cancer cell lines expressed high affinity IL-4R (Kd = 200 pM). Cross-linking experiments revealed a major band of 140 kDa and a broad band at 70 kDa. While the common gamma chain of IL-2R is associated with IL-4R in immune cells and is similar in size to the 70-kDa protein, this chain was not expressed in these colon cancer cells. Interestingly, IL-13, which has many functions similar to IL-4, inhibited 125I-IL-4 binding to both the 140- and 70-kDa molecules. Next, we investigated the mechanism of IL-4-induced signal transduction in colon cancer cells. After stimulation with IL-4, a 170-kDa band was primarily phosphorylated within 1 min of exposure and was identified as insulin receptor substrate-1. In addition, by immunoprecipitation assay, three other phosphorylated bands were identified as JAK1, JAK2, and Tyk2 tyrosine kinases. The phosphorylation of JAK1 and JAK2 was induced by IL-4 stimulation; however, Tyk2 was constitutively phosphorylated, and IL-4 treatment further augmented this phosphorylation. The kinetics and in vitro kinase assays demonstrated that JAK1, JAK2, and Tyk2 were phosphorylated within minutes and that JAK1 and JAK2 were activated after IL-4 exposure. Contrary to observations in immune cells. JAK3 mRNA was neither detected in colon cancer cells nor did IL-4 treatment cause phosphorylation of JAK3. These data indicate that in colon carcinoma cells JAK1, JAK2, Tyk2, and insulin receptor substrate-1 are phosphorylated after IL-4 stimulation. In addition, as is the case in lymphoid cells, IL-4 activated and phosphorylated signal transducers and activators of transcription (IL-4-STAT or STAT-6) protein in both colon cancer cell lines. These results indicate that the IL-4R complex is composed of different subunits in different tissues and shares a component with the IL-13R complex. In addition, we demonstrate for the first time that like its family members (e.g. IL-3 and GM-CSF), IL-4 can phosphorylate and activate JAK-2 kinase.
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PMID:Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. 853 May 27

We have recently reported that IL-13R may share a component with IL-4R. Here we report that both IL-4 and IL-13 share signaling events in human colon carcinoma cell lines (HT-29 and WiDr). IL-13 caused rapid phosphorylation of the three out of four members of the known Janus family of kinases (JAKs). We show that JAK2 kinase is rapidly phosphorylated and activated in response to IL-13. Within 1 min of activation, JAK2 was phosphorylated, and peaked in 10 min. In addition, IL-13 phosphorylated insulin response substrate-1, IL-4R p140, JAK1, and Tyk2, but not JAK3 kinase. IL-4 also stimulated all three kinases and substrates, but unlike in immune cells, IL-4 did not involve JAK3 activation for its signaling in colon cancer cell lines. Furthermore, JAK2 associated with the IL-4R p140 before and after stimulation with IL-13. Both IL-13 and IL-4 induced phosphorylation of IL-4 STAT (STAT6) but not STAT1, STAT3, or STAT5. 125I-IL-13 did not bind to colon cancer cell lines, but unlabeled IL-13 competed for the binding of 125I-IL-4. Our data suggest that IL-13 utilizes IL-4R and its signaling pathway, and JAK2 may play an important role in the function of IL-4R and IL-13R in colon cancer cells.
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PMID:IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. 860 18

Lck protein is expressed in some colon carcinoma cell lines but its expression in colon cancer cells in vivo has not been clarified. LCK transcription is regulated from two distinct promoters and initiated exclusively from the downstream promoter in colon carcinoma cell lines in contrast to peripheral lymphocytes. We investigated the expression of the downstream promoter-initiated LCK transcript in 18 colorectal primary cancer and normal mucosae, and two hepatic metastases, using a RNase protection assay with the EcoRI-BglII fragment of human LCK cDNA, YT16. In normal tissues, only traces of the LCK transcript were detected. The expression of the LCK transcript was augmented in 3/18 cancer specimens. The relative level of the LCK transcript in the cancer tissue compared to the average value of normal adjacent tissue was 10-60 in 3 cases, and 3-10 in 7 cases. One hepatic metastasis expressed more LCK message than the primary lesion. Our results indicate that the LCK message is strongly expressed in some colorectal cancers.
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PMID:Augmented expression of LCK message directed from the downstream promoter in human colorectal cancer specimens. 886 6

We have examined the function of the epidermal growth factor (EGF) receptor, c-Src and focal adhesion kinase (FAK) in the progression of colon cancer using an in vitro progression model. A non-tumorigenic cell line was derived from a premalignant colonic adenoma (PC/AA) from which a clonogenic variant was established (AA/C1). Following sequential treatment with sodium butyrate and the carcinogen N-methyl-N'-nitro-N-nitro-soguanidine an anchorage-independent line was isolated which, with time in culture, became tumorigenic when injected into athymic nude mice (AA/C1/SB10). We have shown that both EGF receptor and FAK protein levels were elevated in the carcinoma cells as compared to the adenoma cells, while the expression and activity of c-Src were unaltered during the adenoma to carcinoma transition. EGF induced the movement of the carcinoma cells into a reconstituted basement membrane which was not seen with the premalignant adenoma cells. This increased motility was accompanied by an EGF-induced increase in c-Src kinase activity, relocalisation of c-Src to the cell periphery and phosphorylation of FAK in the carcinoma cells but not in the adenoma cells. This suggests that c-Src plays a role in the biological behaviour of colonic carcinoma cells induced by migratory factors such as EGF, perhaps acting in conjunction with FAK to regulate focal adhesion turnover and tumour cell motility. Furthermore, although c-Src has been implicated in colonic tumour progression, we demonstrate here that in the adenoma to carcinoma in vitro model c-Src is not the driving force for this progression but co-operates with other molecules in carcinoma development.
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PMID:A role for epidermal growth factor receptor, c-Src and focal adhesion kinase in an in vitro model for the progression of colon cancer. 901 14

The human colon adenocarcinoma cell lines Colo 201 and Colo 205 lose adhevise capacity to the extracellular matrix (ECM) and take on a round and floating cell shape. Treatment of these cells with all-trans-retinoic acid (RA) results in inhibition of growth and in a marked increase in the production of carcinoembryonic antigen, thereby indicating that the cells undergo differentiation. This RA-induced differentiation was accompanied by a large increase in the degree of cell adhesion with localization of E-cadherin molecules at cell-cell contact sites. We examined several adhesion molecules involved in cell-cell and cell-ECM interaction by immunoblotting, but no change in E-cadherin, intercellular adhesion molecule-1, or CD44 was observed in RA-treated Colo 201 cells. Although the adhesion of Colo 201 cells to ECM depends on the Arg-Gly-Asp sequence, levels of integrins, alpha 2, alpha 3, alpha 5, alpha V, and beta 1 in differentiated adherent cells were similar to those in untreated cells. In contrast to equivalent amounts of cell surface adhesion molecules before and after differentiation, intracellular focal adhesion kinase (FAK) was markedly induced during RA treatment, and the increase in FAK resulted in elevation of tyrosine-phosphorylated FAK. These findings suggest a role for FAK in activation of cell adhesion of RA-induced differentiation of these colon cancer cells. This may serve as an appropriate model to examine the mode of activation of the adhesive capacity of cancer cells.
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PMID:Acquisition of cell adhesion and induction of focal adhesion kinase of human colon cancer Colo 201 cells by retinoic acid-induced differentiation. 956 10

The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c-Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human cancers. c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver. Studies of the mechanism of c-Src regulation have suggested that c-Src kinase activity is downregulated by phosphorylation of a critical carboxy-terminal tyrosine (Tyr 530 in human c-Src, equivalent to Tyr 527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region. We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis. These results provide, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.
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PMID:Activating SRC mutation in a subset of advanced human colon cancers. 998 70

The Galbeta1-3GalNAcalpha (TF antigen)-binding lectin (ABL) from the common edible mushroom (Agaricus bisporus) has a potent anti-proliferative effect without any apparent cytotoxicity. This unusual combination of properties prompted investigation of its mechanism of action. In contrast to soluble lectin, agarose-immobilized, and hence noninternalizable ABL had no effect on proliferation of HT29 colon cancer cells. Electron microscopy of HT29 cells incubated with fluorescein- and gold-conjugated ABL showed internalization of the lectin into endocytotic vesicles and multivesicular bodies. Confocal microscopy showed perinuclear accumulation of fluorescein isothiocyanate-conjugated lectin, which also inhibits HT29 cell proliferation, raising the possibility that the lectin might interfere with nuclear pore function. Transport of heat shock protein 70 into the nucleus in response to heat shock was blocked by preincubation of HT29 cells for 6 h with 40 micrograms/ml ABL. In digitonin-permeabilized cells, nuclear uptake of bovine albumin conjugated to a nuclear localization sequence (NLS)-containing peptide was also inhibited by a 15-min preincubation with 40-100 micrograms/ml ABL. In contrast, serum-stimulated nuclear translocation of mitogen-activated protein kinase, which is NLS-independent, was not affected by pretreatment of cells with the lectin. These results suggest that the anti-proliferative effect of ABL is likely to be a consequence of the lectin trafficking to the nuclear periphery, where it blocks NLS-dependent protein uptake into the nucleus.
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PMID:Edible mushroom (Agaricus bisporus) lectin, which reversibly inhibits epithelial cell proliferation, blocks nuclear localization sequence-dependent nuclear protein import. 998 31

For people immunosuppressed by human immunodeficiency virus (HIV), we expect an increase in cancer incidence similar to that documented in transplant patients. We examined the cancer spectrum in an HIV-infected cohort, specifically malignancies not currently associated with acquired immunodeficiency syndrome (AIDS), in relation to the general population. Cancer incidence data for residents of Harris County, Texas, diagnosed between 1975 and 1994, were linked to HIV/AIDS registry data by Soundex code and date of birth to identify malignancies in an HIV-infected cohort of 14,986 persons. Incidence of cancer in this cohort was compared to the general population by standardized incidence ratio (SIR) analysis. From the HIV-infected cohort, 2289 persons (15%) were identified as having one or more malignancies, with 97% occurring in males. The linkage alone identified 29.5% of the malignancies, of which only 28.7% were diagnosed in males. Adjusting for age, HIV-infected men and women had incidences of cancer that were 16.7 [95% confidence interval (CI) 16.1-17.3] and 2.9 (95% CI 2.3-3.7) times that expected for the general population of Harris County, Texas. Besides Kaposi's sarcoma, non-Hodgkin's lymphoma, cervix cancer and brain lymphoma, non-AIDS related malignancies of Hodgkin's lymphoma, non-melanotic skin cancer in males and colon cancer in females, exhibited significant SIRs of 5.6 (95% CI 3.6-8.4), 6.9 (95% CI 4.8-9.5) and 4.0 (95% CI 1.1-10.2). Increased incidences of lung, prostate and breast malignancies were not seen in this HIV cohort. Persons infected with HIV appear to be at increased risk for the non-AIDS related malignancies, Hodgkin's lymphoma, non-melanotic skin cancer in males and colon cancer in females.
Int J STD AIDS 1999 Dec
PMID:HIV-related malignancies: community-based study using linkage of cancer registry and HIV registry data. 1063 60


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