Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calpactin I (annexin II) light chain gene messages were expressed in the DiFi and HT-29 human colon cancer cell lines, as well as in the diploid lung fibroblast cell line WI-38. However, expression of an approximately 1.0 kb transcript was stronger in DiFi and HT-29 cells than in WI-38 cells. The moderate to strong expression of such transcripts in DiFi and HT-29 cells indicates that the calcium binding protein, calpactin I, may be abundant in colon carcinoma cells. Calpactin I is the major substrate of pp60v-src, a tyrosine-specific protein kinase encoded by v-src, whose cellular homologue c-src also codes for a tyrosine kinase (pp60c-src), known to be activated in colon carcinomas and in cell lines derived from them (including HT-29). Abundance of calpactin I in such cells is consistent with the possibility that activation of the pp60c-src tyrosine kinase contributes to the origin of human colon cancers.
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PMID:Expression of the gene coding for the light chain of calpactin I (annexin II) in cell lines DiFi, HT-29, and WI-38. 128 33

Two in vivo and one in vitro studies were performed to evaluate the chemoprotective role of calcium during the early period of azoxymethane (AOM) induction. In the first set of experiments, groups of male Fischer 344 rats were s.c. injected with either AOM (20 mg/kg) or water (controls) and sacrificed immediately (0 time), and 1, 3, 5, and 7 days postinjection. In the second set of experiments, animals were injected with the same dose of AOM and subsequently pair-fed with rat chow containing either calcium carbonate or diet devoid of added calcium. The amount of calcium consumed was calculated to be 250 mg/kg b.w. In both experiments, colonic mucosa was assayed for ornithine decarboxylase (ODC). In addition, tyrosine kinase (Tyr-k) activity as well as tyrosine specific phosphorylation of membrane proteins were determined. Results revealed that maximal stimulation by AOM of ODC and Tyr-k activity occurred 5 days postinjection. This stimulation was significantly suppressed by calcium. AOM also produced an increase in the rate of tyrosine specific phosphorylation of two distinct colonic mucosal membrane proteins with Mr of 57,000 and 59,000. Again, dietary calcium suppressed the stimulation. In the third set of experiments, organ culture was utilized. Methylazoxymethanol, the active metabolite of AOM, was used instead of AOM in this part of the study. Four hour exposure of mucosal explants to methylazoxymethanol (1 microgram/ml) resulted in a significant (20-30%) increase in ODC and Tyr-k activity when compared to controls. Addition of either CaCl2 (2 mumol/ml) or difluoromethylornithine (2 nmol/ml) the irreversible inhibitor of ODC, significantly suppressed the methylazoxymethanol-induced activity of both ODC and Tyr-k. We conclude that calcium may have a chemoprotective role and tyrosine kinases may have a regulatory role in the early stages of AOM induction of colon cancer.
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PMID:Attenuation of azoxymethane-induced colonic mucosal ornithine decarboxylase and tyrosine kinase activity by calcium in rats. 279 Aug 2

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a high incidence of colon cancer. Dysplasia is a precursor to carcinoma and a predictor of malignant potential; epithelia containing high-grade or severe dysplasia is most likely to develop cancer. The cellular oncogene c-src and its viral homologue v-src (the transforming gene of Rous sarcoma virus) encode 60-kD cytoplasmic, membrane-associated protein tyrosine kinases. For the viral protein or transforming mutants of the cellular protein (Src), a close correlation exists between elevated tyrosine kinase activity and malignant transformation of cells. Previously, we and others observed elevated Src activity in sporadic colon carcinomas and benign adenomas at greatest risk for developing cancer (those with large size, villous architecture, and/or severe dysplasia). Here we report that Src activity and protein abundance are also elevated in neoplastic UC epithelia. Activity is highest in malignant and severely dysplastic epithelia, and 6-10-fold higher in mildly dysplastic than in nondysplastic epithelia. Thus, Src activity is elevated in premalignant UC epithelia, which is at greatest risk for developing cancer. The data suggest that activation of the src proto-oncogene is an early event in the genesis of UC colon cancer.
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PMID:Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis. 750 41

Staurosporin, a broad-spectrum kinase inhibitor, induced cell spreading in a human colon cancer cell line, Colo 201. On collagen and laminin, cell spreading was induced in more than 90% of the cells and was dependent on very late activation antigen-3, as shown by an antibody inhibition assay. Cell spreading required divalent cations and showed the order of preference Mn2+ > Mg2+ > Ca2+. On fibronectin, only about 30% of the cells were observed to spread, and spreading occurred via a non-integrin, RGD-independent pathway. Staurosporin-induced spreading was inhibited by treatment with tyrosine kinase inhibitors herbimycin A and methyl 2,5-dihydroxycinnamate. Despite the presence of staurosporin, seven proteins (220, 175, 150, 98, 62, 58, and 45 kDa) showed increased levels of tyrosine phosphorylation in association with cell adhesion. Two of these (58 and 220 kDa) were identified by immunoprecipitation as Src product and tensin, respectively. Flow cytometric analysis showed that the Colo 201 cells expressed the alpha 2, alpha 3, alpha 6, and beta 1 chains of integrin, but expression of these chains was not influenced by staurosporin. Immunofluorescence microscopy revealed that the alpha 3 chain, diffusely expressed on the cell surface in the absence of staurosporin, was concentrated at focal adhesion plaques after staurosporin treatment. Neither alpha 2 nor alpha 6 was focalized by the treatment.
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PMID:Cell spreading in Colo 201 by staurosporin is alpha 3 beta 1 integrin-mediated with tyrosine phosphorylation of Src and tensin. 753 Jul 22

We tested the potential impact of tyrosine phosphorylation on the expression of the c-myc gene in two colon cancer cell lines, HCT8 and SW837. We found that the protein tyrosine kinase inhibitor genistein causes a decrease in the abundance of c-myc RNA and an inhibition of proliferation with a similar dose response. Geldanamycin, a mechanistically different tyrosine kinase inhibitor, also causes a decrease in both the expression of c-myc RNA and proliferation. Genistein has also been found to inhibit topoisomerase II, but the topoisomerase II inhibitor novobiocin did not lower the expression of c-myc. The most likely interpretation is that inhibition of protein tyrosine kinase activity caused a decrease in c-myc expression in these cells. The impact of tyrosine phosphorylation on the expression of the c-myc gene is further supported by the finding that inhibition of phosphotyrosine phosphatase using orthovanadate causes an increase in the level of c-myc RNA. The effect of genistein on HCT8 cells is not dependent on the synthesis of new protein and does not involve an alteration in the stability of the message. Analysis of transcription in the c-myc gene reveals a more complicated picture with a decrease in initiation and an increase in elongation but no net change in transcription. We speculate that the genistein induced reduction in myc expression is the result of a posttranscriptional intranuclear event(s).
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PMID:Influence of protein tyrosine phosphorylation on the expression of the c-myc oncogene in cancer of the large bowel. 764 26

The c-src proto-oncogene has been implicated in the progression of primary human colorectal carcinoma to hepatic metastasis. To determine if increased pp60c-src tyrosine kinase activity is a colon-specific phenomenon present in colorectal metastases to all sites, the pp60c-src-specific kinase activity of noncolon tumor metastases to the liver was compared to that of colorectal liver metastases. Activity of extrahepatic colon carcinoma metastases was compared to that of colorectal liver metastases as well as that of normal colonic mucosa. The specific activity of pp60c-src in multiple synchronous metastases from colon carcinoma was also examined. Tyrosine kinase activity was determined by immune complex kinase assay; protein levels were determined by immunoblotting. Specific activity was calculated for each group by dividing the total activity by protein level. Colon carcinoma metastases to the liver had significantly (P < 0.04) increased pp60c-src activity with an average 2.2-fold increase over normal mucosa. In contrast, noncolon tumor metastases to the liver showed minimal pp60c-src kinase activity. Extrahepatic colorectal metastases demonstrated significantly increased (P < 0.005) pp60c-src activity with an average 12.7-fold increase over normal mucosa. When compared to colon liver metastases, extrahepatic colorectal tumor metastases show a significant difference in activity (P < 0.05) with an average 5.7-fold increase. Examination of multiple synchronous colon carcinoma metastases confirmed these results. In summary, we conclude that (1) the activation of pp60c-src between primary tumors and metastases is specific to colon metastases, and (2) although pp60c-src activity is significantly increased in colorectal metastases, site-specific differences in the magnitude of activity are evident.
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PMID:Site-specific differences in pp60c-src activity in human colorectal metastases. 768 14

In this article we have reviewed and discussed the results of our investigation of lipid metabolites as modulators of epidermal growth factor (EGF) signaling pathways. We have studied epidermal growth factor-dependent mitogenesis in BALB/c 3T3 and Syrian hamster embryo (SHE) cells in culture. We observed that EGF stimulates the formation of prostaglandins in BALB/c 3T3 cells and their formation appears to be necessary for EGF dependent mitogenesis. EGF did not stimulate PGE2 formation in SHE cells and in fact, exogenously added PGE2 inhibited mitogenesis. In both cell lines, EGF stimulated the formation of lipoxygenase-derived 13(S)-hydroxyoctadecadienoic acid (13-HODE) and inhibition of 13-HODE formation attenuated mitogenesis. The addition of 13-(S)-HODE enhanced EGF-dependent mitogenesis but when added alone, the compound was not mitogenic. Other metabolites, including lipoxygenase metabolites of arachidonic acid, were either weak simulators of EGF-dependent mitogenesis or essentially inactive. The 13(S)-HODE appears to be formed by an apparently unique lipoxygenase that is regulated by the tyrosine kinase activity of the EGF receptor. The mechanisms by which lipids, particularly the lipoxygenase-derived linoleic acid metabolites, modulate the EGF signaling pathways leading to cell proliferation is discussed. The possible significance of lipoxygenase and prostaglandin H synthase-dependent metabolism of unsaturated fatty acids in breast and colon cancer is also discussed.
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PMID:Cellular proliferation and lipid metabolism: importance of lipoxygenases in modulating epidermal growth factor-dependent mitogenesis. 771 98

Using a PCR-based cloning technique, we have isolated a series of DNA fragments coding for tyrosine kinases that are expressed in a metastatic human colon tumor, and have subsequently analyzed their expression pattern at the protein level in human tumors. We identified both the alpha and the beta forms of the platelet-derived growth factor receptor (PDGFR), axl and 8 other genes, including 3 cytoplasmic tyrosine kinases. To study their expression in human colon cancer, we performed Western blots of matched sets of normal tissues and of carcinomas from the same patient. These revealed that the alpha-PDGFR migrates predominantly as a 200-kDa band in 8/8 normal tissues, and as a 170-kDa band in 17/17 malignant tissues, as well as in colonic polyps, suggesting that expression of an isoform of this receptor may be a marker for the progression of colon cancer. Additional studies showed that the Axl receptor tyrosine kinase was expressed at 10-fold higher levels in a peritoneal metastatic nodule than in other normal and malignant tissues. Immunohistochemistry revealed Axl over-expression specifically in the malignant cells of the tumor. This indicates that over-expression and possibly a differential processing event of tyrosine kinase receptors may be involved in colon cancer, and that they are potential markers for the progression of this disease.
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PMID:Receptor tyrosine kinases expressed in metastatic colon cancer. 789 47

Although several tyrosine kinase-type growth factor receptors have been demonstrated in human colonic epithelial cells, the full spectrum of growth factor receptors has not been identified. Low stringency screening of a complementary DNA library prepared from the human colon cancer-derived cell line HT-29 with a probe containing the tyrosine kinase domain of human c-src kinase led to the identification and isolation of a clone containing a receptor class tyrosine kinase. This putative receptor was found to be identical to the human fibroblast growth factor receptor 3 (FGFR3) except for a region of 150 nucleotides (50 amino acids) encoding the presumptive ligand-binding domain, where it exhibited only 32% homology with the previously described FGFR3. The variant domain corresponded precisely to the splicing junctions of the exon encoding the carboxyl terminal half of the third immunoglobulin-like domain, suggesting that two forms of FGFR3 result from splicing of alternate exons in a manner similar to that previously found for FGFR1 and FGFR2. By prior convention, the previously reported from of FGFR3 was designated IIIc due to its high degree of homology with the IIIc domain of FGFR1 (83% homology) and the IIIc domain of FGFR2 (81% homology). However, the ligand-binding domain of FGFR3 found in the HT-29 cell line was more highly divergent from all previously reported FGFR immunoglobulin-like domain IIIs than any other two members of this receptor family. Therefore, we propose to designate the newly reported form as the FGFR3 IIIb variant. Genomic polymerase chain reaction confirmed that the IIIb-containing exon occupies a position 5' relative to the IIIc-containing exon within the FGFR3 gene. Northern blot analysis using a probe encompassing sequences unique to the FGFR3 IIIb mRNA confirmed the expression of a 4.4-kilobase transcript in two colon cancer-derived cell lines as well as normal human colonic mucosa. Using a technique combining reverse transcriptase polymerase chain reaction with restriction endonuclease digestion, cell lines, primary cells, and tissues were assessed for IIIb and IIIc transcripts; expression of the IIIb variant was associated with an epithelial lineage, while the IIIc variant was expressed predominantly in nonepithelial cells and tissues.
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PMID:Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. 792 41

All-trans-retinoic acid (RA), like insulin-like growth factor I (IGF-I) and tamoxifen, inhibit invasion of human MCF-7/6 mammary cancer cells in vitro. For tamoxifen and for IGF-I, activation of the invasion-suppressor function of the E-cadherin/catenin complex was shown to be the most probable mechanism of the anti-invasive action. We did a series of experiments to determine whether the anti-invasive effect of RA also implicated the invasion-suppressor E-cadherin/catenin complex. Human MCF-7/6 mammary and HCT-8/R1 colon cancer cells, both with a dysfunctional E-cadherin/catenin complex, were treated with RA and the function of the complex was evaluated through Ca(2+)-dependent fast aggregation. Fast aggregation of both MCF-7/6 and HCT-8/R1 cells was induced by 1 microM RA. This effect was abolished by antibodies against E-cadherin. RA-induced fast aggregation was not sensitive to cycloheximide, tyrosine kinase inhibitors or antibodies against IGF-I or against the IGF-I receptor. RA did not stimulate IGF-I receptor phosphorylation or alter the E-cadherin/catenin complex, as evidenced by immunoprecipitation. RA up-regulates the function of the invasion-suppressor complex E-cadherin/catenin. Its action mechanism is different from that of IGF-I. RA may act as an anti-invasive agent with unique mechanisms of action.
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PMID:Activation of the E-cadherin/catenin complex in human MCF-7 breast cancer cells by all-trans-retinoic acid. 851 58


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