Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trans-tamoxifen (TAM) has been used successfully in therapy for estrogen-dependent human breast tumors and prevention of their recurrence. The mechanism of this prevention was thought to be due to the interference of TAM with estrogen promotion. TAM has a wider anticarcinogenic action that is similar to other chemopreventive agents in that it suppresses tumor promotion in 2-stage carcinogenesis by interfering with the action of protein kinase C. We report that TAM (5 microM) totally inhibits hydrogen peroxide (H2O2) formation by 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-treated human neutrophils. Interestingly, beta-estradiol (10 microM) also slightly inhibits the oxidative burst of neutrophils. Pretreatment of neutrophils with varying amounts of TAM and beta-estradiol caused additive inhibition of H2O2 formation by the 2 agents. 4-Hydroxy-tamoxifen, a metabolite with the highest affinity for the estrogen receptor, was only as inhibitory as beta-estradiol. Other derivatives (cis-, N-desmethyl-, and N-desdimethyl-tamoxifen) with low biological activities had a smaller effect on H2O2 formation. TPA-treated neutrophils were shown to contain 5-hydroxymethyl uracil (HMU). TAM prevented the TPA-induced formation of HMU in other cells. Like TPA, dietary fat, which is a risk factor for breast cancer, induces formation of HMU in the DNA of human white blood cells. TAM may suppress the dietary fat-induced HMU in the same manner at it does in TPA-induced neutrophils.
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PMID:Tamoxifen suppresses tumor promoter-induced hydrogen peroxide formation by human neutrophils. 151 53

The mouse skin model of multistage carcinogenesis has for many years provided a conceptual framework for studying carcinogenesis mechanisms and potential means for inhibiting specific stages of carcinogenesis. The process of skin carcinogenesis involves the stepwise accumulation of genetic change ultimately leading to malignancy. Initiation, the first step in multistage skin carcinogenesis involves carcinogen-induced genetic changes. A target gene identified for some skin tumor initiators is c-Ha-ras. The second step, the promotion stage, involves processes whereby initiated cells undergo selective clonal expansion to form visible premalignant lesions termed papillomas. The process of tumor promotion involves the production and maintenance of a specific and chronic hyperplasia characterized by a sustained cellular proliferation of epidermal cells. These changes are believed to result from epigenetic mechanisms such as activation of the cellular receptor, protein kinase C, by some classes of tumor promoters. The progression stage involves the conversion of papillomas to malignant tumors, squamous cell carcinomas. The accumulation of additional genetic changes in cells comprising papillomas has been correlated with tumor progression, including trisomies of chromosomes 6 and 7 and loss of heterozygosity. The current review focuses on the mechanisms involved in multistage skin carcinogenesis, a summary of known inhibitors of specific stages and their proposed mechanisms of action, and the relevance of this model system to human cancer.
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PMID:Multistage carcinogenesis in mouse skin. 152 55

A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin caused an induction of epidermal ornithine decarboxylase (ODC) activity. When mice were topically pretreated with staurosporine, a most potent protein kinase C inhibitor, 6-84 h prior to TPA treatment, TPA-caused ODC induction was markedly enhanced. The enhancement of TPA-caused ODC induction by staurosporine was most pronounced when the time interval between staurosporine and TPA treatment was 36 h. Staurosporine elicited this enhancing effect in a dose-related manner. Staurosporine by itself also induced epidermal ODC activity. But the activity induced was very slight and would not directly contribute to the enhancing effect of this compound. Although staurosporine markedly augmented TPA-caused ODC induction, staurosporine-caused ODC induction was not augmented by this compound. Other protein kinase C inhibitors, such as 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, sphingosine and palmitoylcarnitine did not mimic the enhancing effect of staurosporine. These results indicate that the enhancement of ODC induction by staurosporine is specific for the induction caused by TPA and that this enhancing effect is not related to the protein kinase C inhibitory action of staurosporine. TPA-caused epidermal ODC induction was inhibited by indomethacin, and this inhibition was reversed by prostaglandin E2 (PGE2). Staurosporine-caused ODC induction was also inhibited by indomethacin but the inhibition was not reversed by PGE2, indicating that the mechanism of staurosporine-caused ODC induction is different from that of TPA.
Carcinogenesis 1992 Mar
PMID:Staurosporine, a potent protein kinase C inhibitor, augments phorbol ester-caused ornithine decarboxylase induction in mouse epidermis. 154 24

We examined protein kinase C (PKC) activity in the cytosolic and particulate fractions of homogenates obtained from 25 colorectal adenomas and adjacent normal mucosa in patients with colorectal carcinoma. The total PKC activity of colorectal adenomas was significantly reduced compared with that of normal mucosa in all cases (122 +/- 45.8 vs 174 +/- 50.5 pmol min-1 mg-1) (means +/- s.d.) (P less than 0.001). The particulate fraction PKC activity of adenomas was also significantly lower than in normal mucosa (71.4 +/- 31.3 vs 115 +/- 39.6 pmol min-1 mg-1) (P less than 0.001). Adenomas were classified by size, histological type and degree of dysplasia. The average particulate PKC activity ratio (adenoma/normal mucosa) of tubulovillous adenomas or those with severe dysplasia was significantly reduced compared with that of tubular adenomas or tumours with mild and moderate dysplasia (both P less than 0.001), while there were no significant differences in the cytosolic PKC activity ratio. The particulate PKC activity ratio decreased significantly with increasing adenoma size (P less than 0.001), while the cytosolic ratio again showed no difference. These findings suggested that the particulate PKC activity ratio had a possible correlation with the malignant potential of colorectal adenomas and that this ratio may be a useful biological indicator of colorectal carcinogenesis.
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PMID:Correlation between protein kinase C activity and histopathological criteria in human colorectal adenoma. 158 95

In previous experiments we have shown that acute (30 minutes) exposure to phorbol esters or other protein kinase C activators causes increased transepithelial permeability, specifically by the increased paracellular permeability through tight junctions. However, the role of protein kinase C activators in carcinogenesis is predicted upon a chronic exposure of an effective dose at frequent intervals for a prolonged period of time. We therefore sought to determine the effect of chronic phorbol ester exposure on transepithelial permeability by exposing cells of the polar renal epithelial cell line, LLC-PK1, to phorbol esters for time periods as long as 16 weeks. The following changes ensued: (1) after the initial drop in transepithelial resistance due to phorbol ester exposure, i.e., an increase in transepithelial permeability (in the acute phase of exposure), an adaptive response occurs as transepithelial resistances in chronically exposed cultures recover to approximately 50% of control values, (2) the cell sheets in chronically exposed cultures lose their acute responsiveness of transepithelial permeability to phorbol ester exposure, (3) cell sheet architecture changes as cells occasionally multilayer and actual polyp-like cell masses appear at high frequency, and (4) cytosolic protein kinase C activity decreases to 50% of control level with acute exposure and then is further decreased to less than 1% of control level in chronically treated cells; membrane-associated PKC activity is not as sharply decreased. The possible role of transepithelial permeability in carcinogenesis and the value of chronically treated epithelial cell cultures as a model for two-stage carcinogenesis are discussed.
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PMID:Effects of acute vs. chronic phorbol ester exposure on transepithelial permeability and epithelial morphology. 161 21

Triphenylmethane (TPM) was found to inhibit 3-methyl-cholanthrene-induced neoplastic transformation of 10T1/2 cells in a dose-dependent manner (ED50 = 2.8 microM). This activity was independent of any effect on intercellular communication and did not appear to be directly related to the general antioxidant properties of TPM as measured by cellular thiobarbituric acid-reactive substances. Triphenylmethanol (TPMOL) and diphenylmethane also inhibited transformation (ED50 = 6.9 and 90 microM respectively). TPM had no effect on the proliferation of exponentially growing cells. At higher concentrations TPM and its analogues enhanced plating efficiency of cells indicating no significant toxicity for these compounds at levels up to 50 microM. The inhibitory effects of TPM on transformation were reversible when TPM was removed from the medium. While TPM had no effect on the growth of fully transformed cell lines, it was able to inhibit the growth of 1/3 neoplastic foci in the presence (but not absence) of 10T1/2 cells. TPM was found to stimulate protein kinase C (PKC) activity for both crude C3H10T1/2 cytosolic PKC and purified PKC obtained from rat brain. The ability of TPM to stimulate PKC activity appeared to be dependent on [CaCl2] and the order of reagent addition in the assay. Tamoxifen, a structurally related compound to TPM, was also found to enhance PKC activity over the same concentration range but was less potent than TPM. The biological effects of TPM and related compounds indicate that they function in a manner distinct from other highly unsaturated transformation inhibitors such as carotenoids and retinoids. The inability of triphenylene to inhibit transformation suggests that a reactive methyl carbon may be essential for activity.
Carcinogenesis 1992 Jul
PMID:Inhibition of cellular transformation by triphenylmethane: a novel chemopreventive agent. 163 75

The levels of protein kinase C (PKC) activity, PKC isozymes, as well as the level of endogenous diacylglycerols (DAG) were examined in early emergence mouse skin papillomas and compared to the levels in the epidermis. The papillomas were derived from a two-stage carcinogenesis protocol in which mice were initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted twice weekly for only 12 weeks with 12-O-tetradecanoylphorbol-13-acetate (TPA). As expected, greater than 90% of these early emergence papillomas contained an activated Ha-ras gene with an A----T transversion in the 61st codon. There was a TPA-independent, irreversible decrease in total PKC activity (70%) in the early emergence papillomas compared to that in the epidermis. Immunoblot analysis of epidermis and papillomas taken 4 weeks following the cessation of TPA treatment, a time when PKC catalytic activity has completely recovered to control level in epidermis but not in papillomas, revealed that the levels of PKC-alpha and PKC-beta 2 were dramatically decreased in the cytosol of the papillomas, while the levels of these two isozymes in the particulate fraction were approximately equal to the epidermis. PKC-delta, -epsilon and -zeta immunoreactive proteins were present in both epidermis and papillomas and only minor changes were observed in the papillomas. PKC-delta and PKC-epsilon displayed a particulate fraction localization in both the epidermis and papillomas, while PKC-zeta was found in both subcellular fractions. We were unable to detect PKC-gamma in mouse epidermis or papillomas. Since the level of DAG has been shown to be elevated in some ras-transformed cells, we examined DAG levels in the papillomas, as an increased DAG level could explain the constitutive decreases in the levels of PKC. Measurements of cellular DAG indicated that there was no elevation in the total pool of DAG in the early emergence papillomas. These data demonstrate an irreversible decrease in and alteration of the subcellular distribution of PKC-alpha and beta 2 in DMBA-initiated/TPA-promoted papillomas. These changes are TPA-independent, and occur in the absence of an elevation in the total pool of endogenous DAG. These alterations of PKC isozymes may be important early events in multistage tumorigenesis.
Carcinogenesis 1992 Jul
PMID:Alterations in protein kinase C isozymes alpha and beta 2 in activated Ha-ras containing papillomas in the absence of an increase in diacylglycerol. 163 76

Cryptoporic acids D and E, isolated from the fungus Cryptoporus volvatus, are inhibitors of superoxide anion radical release. Cryptoporic acid E inhibited tumor promotion of okadaic acid in two-stage carcinogenesis experiments on mouse skin, initiated with 7,12-dimethylbenz[a]anthracene. Treatment with cryptoporic acid E using two different doses per application, 1 (1.2 mumol) and 5 mg (5.9 mumol), reduced the percentage of tumor-bearing mice from 73.3 to 53.3% and 20.0%, and the average number of tumors per mouse from 4.2 to 2.3 and 0.5 respectively in week 20 of tumor promotion. However, cryptoporic acid D slightly enhanced tumor promotion rather than inhibition of okadaic acid. Cryptoporic acid D was expected to have additional biochemical activities, such as activation of protein kinases. Cryptoporic acid D at concentrations of up to 100 microM activated protein kinase C and stimulated other protein kinase activity in vitro, whereas cryptoporic acid E did not. These two compounds provided differential effects on tumor promotion of okadaic acid on mouse skin.
Carcinogenesis 1991 Jun
PMID:Differential effects of cryptoporic acids D and E, inhibitors of superoxide anion radical release, on tumor promotion of okadaic acid in mouse skin. 164 82

To determine the mechanisms of cell signalling by asbestos in epithelial cells of the respiratory tract, the activity of protein kinase C (PKC) was examined in hamster tracheal epithelial (HTE) cells exposed to mitogenic concentrations of crocidolite asbestos. In the histone phosphorylation assay, asbestos significantly increased activity of PKC associated with the membrane fraction of HTE cells. However, in contrast to 12-O-tetradecanoylphorbol-13-acetate, which caused redistribution of almost all PKC activity from the cytosolic to the membrane fraction, the majority of the PKC activity was associated with the cytosolic fraction at all time periods examined. Asbestos did not inhibit binding of [3H]phorbol-12,13-dibutyrate to intact HTE cells, whereas binding was inhibited by the phorbol compounds phorbol dibutyrate and phorbol dibenzoate. Thus, crocidolite-induced activation of PKC does not appear to be mediated through the same mechanism as classical phorbol ester tumor promoters, compounds which activate PKC by structurally resembling diacylglycerol.
Carcinogenesis 1991 Aug
PMID:Activation of protein kinase C by crocidolite asbestos in hamster tracheal epithelial cells. 165 Feb 93

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


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