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)

Addition of transforming growth factor alpha (TGF-alpha) to cultured human keratinocytes results in enhanced expression of TGF-alpha mRNA. This phenomenon of TGF-alpha autoinduction is also observed in a TGF-alpha responsive colon cancer cell line, LIM 1215. In the present study, regulation of TGF-alpha autoinduction is examined in these two cell types. In human keratinocytes, but not in LIM 1215 cells, the increase in steady-state TGF-alpha mRNA following administration of TGF-alpha is due to stabilization of the 4.8-kilobase TGF-alpha transcript, as determined by actinomycin D decay curves. Nuclear run-on experiments confirmed transcriptional control in LIM 1215 cells. Basal and TGF-alpha-stimulated TGF-alpha expression is mediated, at least in part, through a protein kinase C-dependent pathway in both cell types, as determined by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), which attenuates TGF-alpha mRNA accumulation. In the keratinocytes, but not in the LIM 1215 cells, basal TGF-alpha expression is mediated through an epidermal growth factor receptor-dependent pathway, as determined by antibody blockade of the epidermal growth factor receptor. Thus, differential regulation of TGF-alpha autoinduction exists in these nontransformed and transformed epithelial cell types.
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PMID:Differential regulation of transforming growth factor alpha autoinduction in a nontransformed and transformed epithelial cell. 141 97

Our previous work on protein kinase C (PKC) and colon cancer has shown altered levels of PKC activity in human colon tumors, as well as activation of PKC by colon tumor promoters such as bile acids. To understand further the role of PKC in colon carcinogenesis, we analyzed the expression of phorbin, a gene induced by PKC activation, in a series of different stages of human colon tumors. As shown by northern blot analyses of poly (A)+ RNA, higher levels of phorbin RNA were seen in 26 colon tumor samples than in their adjacent normal colonic mucosa. There also appeared to be a correlation between the abundance of phorbin RNA in the tumors and the extent of invasion (tumor-to-normal tissue phorbin RNA ratio = 4.2, 8.0, and 11.9 for Dukes' A, B, and C, respectively). Phorbin RNA was also abundant in a human colon cancer line (HT29). We also examined the expression of other mitogen-responsive genes (c-myc, ODC, and beta-actin) in a set of 19 colon tumor samples. All tumors displayed significant (mean 3.8-fold) increases in the level of c-myc RNA compared with their adjacent normal colonic mucosa. About 47% and 16% of these tumor samples also showed increased levels of ODC (mean 3.1-fold) and beta-actin (mean 1.6-fold) RNA, respectively. The increased levels of c-myc, ODC, and beta-actin RNA did not correlate with the extent of tumor invasion. Taken together, these results demonstrate that human colon tumors usually display increased levels of both phorbin and c-myc RNAs. The marked increases in phorbin RNA suggest that this could serve as a useful biomarker in studies on human colon cancer.
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PMID:Increased levels of phorbin, c-myc, and ornithine decarboxylase RNAs in human colon cancer. 169 76

To examine whether protein kinase C (PKC) plays a role in mediating growth inhibitory effects of hexamethylene bisacetamide (HMBA) we compared a control H29 colon cancer cell line to a derivative, HT29-PKC7, that overexpresses high levels of PKC beta 1. We found that although HMBA markedly inhibited the growth of the control cells, no inhibition was seen with the HT29-PKC7 cells. On the other hand the tumor promoter 12-0-tetradecanoyl-phorbol-13 acetate inhibited the growth of HT29-PKC7 cells, but no inhibition was seen with the control cells. Maximum inhibition of the growth of both cell lines was obtained by combined treatment with HMBA and TPA. These results may be relevant to the use of HMBA in combination with other agents in the therapy of specific cancers.
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PMID:The modulation of growth by HMBA in PKC overproducing HT29 colon cancer cells. 175 60

Treatment of rodent cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate activates protein kinase C, leading to increased expression of several genes, including a gene originally designated TPA-S1 or phorbin (M. D. Johnson, G. M. Housey, P. T. Kirschmeier, and I. B. Weinstein, Mol. Cell Biol., 7: 2821-2829, 1987). Sequence analysis of this cloned gene indicated homology with human erythroid-potentiating activity and tissue inhibitor of metalloproteinase (TIMP-1). Elevated levels of phorbin mRNA have been observed in human colon tumors (J. G. Guillem, M. F. Levey, L. L. Hsieh, M. D. Johnson, P. LoGerfo, K. A. Forde, and I. B. Weinstein, Mol. Carcinogen., 3: 68-74, 1990) and this increase correlated with the extent of invasion. To further investigate this phenomenon at the protein level, monoclonal antibodies were developed against the recombinant form of TIMP-1. A competitive enzyme-linked immunosorbent assay was developed for quantitation of the TIMP-1 protein in tissue extracts. Elevated levels of TIMP-1 protein were found in 31 human colon tumors, compared to paired samples of adjacent normal mucosa. In a subset of samples, previously analyzed for phorbin mRNA levels (n = 25), there was a good correlation between the abundance of TIMP-1 protein and phorbin mRNA. Immunoaffinity column purification of tumor extracts followed by Western blot analysis was used to confirm the enzyme-linked immunosorbent assay data. These results provide evidence that phorbin and TIMP-1 represent the same gene. In addition, the immunoassays we have developed may be useful in further studies on the role of TIMP-1 in human colon cancer.
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PMID:Immunological quantitation of levels of tissue inhibitor of metalloproteinase-1 in human colon cancer. 193 83

We have found that in 15 of 15 primary human colon tumors there was a significant decrease (by about 40%) in the levels of diacylglycerol when compared to paired adjacent normal mucosa samples. Assays on the same samples indicated that this decrease was seen both in tumors that did and did not display mutations in codon 12 of c-K-ras. These results, taken together with previous studies on protein kinase C, suggest that the protein kinase C signal transduction pathway is suppressed in human colon cancer.
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PMID:Decreased levels of 1,2-sn-diacylglycerol in human colon tumors. 199 99

We investigated the effects that phorbol ester and diacylglycerol protein kinase C (PKC) activators had on the chemosensitivity of the human colon cancer cell line KM12L4a to Adriamycin (ADR), vincristine (VCR), and vinblastine (VLB) and on the intracellular accumulation of those drugs. Exposure of the cells to the PKC activator phorbol-12,13-dibutyrate (PDBu) (15 nM) during a 96-hr in vitro chemosensitivity assay significantly reduced the sensitivity of KM12L4a cells to ADR, VCR, and VLB, but not to 5-fluorouracil. Because a 96-hr treatment with 15 nM PDBu did not down-regulate PKC activity in KM12L4a cells, activation of PKC appeared to be responsible for the observed protection conferred by PDBu. PDBu-induced alterations in drug accumulation may account for its protective effects against these cytotoxic drugs, because both PDBu and the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate significantly reduced accumulation of [3H] VCR and [14C]ADR in the cultured human colon cancer cells. Unsaturated diacylglycerols are structural and functional analogues of phorbol ester PKC activators that are present in the lumen of the colon. We found that treatment of KM12L4a human colon cancer cells with the diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol (OAG) significantly reduced [14C]ADR and [3H]VCR accumulation in the cells. The effects of OAG were dose dependent at physiological diacylglycerol concentrations and were completely reversed by the protein kinase inhibitor H7. OAG, which is rapidly metabolized in cultured cells, did not protect KM12L4a cells against the cytotoxic drugs in our 96-hr in vitro chemosensitivity assay. However, rapid metabolism of diacylglycerols should not limit their capacity to activate PKC in the colonic epithelium in vivo, because that tissue is chronically exposed to replenished supplies of unsaturated diacylglycerols in the intestinal tract. Our results provide evidence that unsaturated diacylglycerols may be environmental factors that contribute to the intrinsic drug resistance of colon cancer in vivo by reducing drug accumulation in the cancer cells.
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PMID:In vitro model for intrinsic drug resistance: effects of protein kinase C activators on the chemosensitivity of cultured human colon cancer cells. 201 56

In this study we examined whether the antiproliferative effects of tumor necrosis factor (TNF)-alpha and beta were associated with the activation of protein kinase C (PKC), using the LoVo human colon cancer cell line which is resistant to both TNFs. In combination with 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of PKC, TNF-alpha caused marked growth inhibition of LoVo cells, but TNF-beta had little antiproliferative effect. There was no difference in the effect when TPA was added 1 h before or 4 h after TNF-alpha administration. A PKC inhibitor, H-7, not only decreased the sensitivity of LoVo cells to TNF-alpha but also caused a slight promotion of cell proliferation and dose-dependently blocked the growth inhibition induced by TNF-alpha and TPA. These results suggested a possible regulatory function of PKC within the TNF-alpha-mediated intracellular signalling pathway. PKC may act at a later stage in the transduction pathway.
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PMID:Differing roles of protein kinase C on the antiproliferative effects of tumor necrosis factor alpha and beta on LoVo cells. 222 8

Tumor-producing phorbol esters [e.g., 12-O-tetradecanoylphorbol-13-acetate (TPA)] induce changes in a human colon cancer cell line, VACO 10MS, that mimic terminal differentiation: a rapid blockade of DNA replication and cell division, a marked increase in cell adhesion properties with striking changes in morphology, and the acquisition of ion-transporting activities. The present report shows that the triggering of this terminal differentiation sequence by TPA is associated with a rapid release of heparan sulfate proteoglycans from the cell surface that is soon followed by an acceleration of proteoglycan synthesis. The activation of the release mechanism is independent of ongoing protein synthesis, whereas the resynthesis of the proteoglycans requires the production of new proteins. A persistent high rate of proteoglycan synthesis and release appears correlated with the progression of the colon cell into the terminal differentiation state. Bryostatin 1, an agent which has been shown previously to block the TPA-induced terminal differentiation of this cell line, also largely prevents the TPA effects on proteoglycan metabolism. Since both TPA and bryostatin 1 produce their effects through the activation of members of the protein kinase C class of enzymes, it is proposed that the differentiation state of these colon cancer cells may be regulated by a differential activation of isozymes or a ligand-directed phosphorylation of proteins that are involved in proteoglycan metabolism.
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PMID:Phorbol esters activate proteoglycan metabolism in human colon cancer cells en route to terminal differentiation. 227 82

Although dietary lipids have been implicated in colon cancer causation, the underlying mechanisms are not known. This paper indicates that when bacteria obtained from normal human feces are incubated with 14C-labeled phosphatidylcholine there is appreciable production of diacylglycerol (DAG), monoacylglycerol, and free fatty acid. Curiously, the production of DAG and monoacylglycerol, but not fatty acid, is strictly dependent on addition of certain bile acids to the incubation system. Among the bile acids tested deoxycholic acid is the most active. Assays of fecal specimens from 10 normal individuals demonstrate a 27-fold interindividual variation in the production of DAG in the in vitro assay system, and also in the absolute levels of DAG present in the same fecal samples. On the other hand, both parameters of DAG are quite constant in repeated fecal samples obtained from the same individual over a period of about 4 months. DAG is a normal physiological activator of protein kinase C, an enzyme that plays a key role in growth control and tumor promotion. We speculate, therefore, that DAG produced by the intestinal microflora might stimulate growth of colonic epithelial cells. Thus an interaction between dietary lipids, bile acids, and specific bacteria in the intestinal lumen could contribute to the risk of colon cancer development in humans.
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PMID:Production of diacylglycerol, an activator of protein kinase C, by human intestinal microflora. 234 May 7

By using a retrovirus-derived vector system, we generated derivatives of the human colon cancer cell line HT29 that stably overexpress a full-length cDNA encoding the beta 1 isoform of rat protein kinase C (PKC). Two of these cell lines, PKC6 and PKC7, displayed an 11- to 15-fold increase in PKC activity when compared with the C1 control cell line that carries the vector lacking the PKC cDNA insert. Both of the overexpresser cell lines exhibited striking alterations in morphology when exposed to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Following exposure to TPA, PKC6 and PKC7 cells displayed increased doubling time, decreased saturation density, and loss of anchorage-independent growth in soft agar; but these effects were not seen with the C1 cells. Also, in contrast to the control cells, the PKC-overproducing cells failed to display evidence of differentiation, as measured by alkaline phosphatase activity, when exposed to sodium butyrate. In addition, the PKC-overexpresser cells displayed decreased tumorigenicity in nude mice, even in the absence of treatment with TPA. These results provide the first direct evidence that PKC can inhibit tumor cell growth. Thus, in some tumors, PKC might act as a growth-suppressor gene.
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PMID:Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression. 238 20


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