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)

Two antitumor antibiotics doxorubicin and daunorubicin were tested for their ability to influence the activation of protein kinase C in human platelets. Daunorubicin was found to inhibit the phosphorylation of the 40 K PKC substrate induced by thrombin and 12-O-tetradecanoyl-phorbol-13-acetate as well as the phosphorylation of the 20 K protein induced by thrombin. The serotonin release associated to these phosphorylative events was also inhibited by daunorubicin. In contrast the effects of doxorubicin, though inhibitory on the release reaction, were always stimulatory of the phosphorylations. Doxorubicin alone was able to induce the phosphorylation of both 40 K and 20 K phosphoproteins in a concentration-dependent manner. Whereas the stimulation by doxorubicin was not influenced by pretreatment with dibutyryl-cyclic-AMP which inhibits the effects of thrombin, this effect was inhibited by daunorubicin, neomycin and stimulated by the diacylglycerol-kinase inhibitor R 59 022. It is proposed that doxorubicin activates the protein kinase C by causing the breakdown of phosphoinositides.
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PMID:Diversity of effects of two antitumor anthracycline analogs on the pathway of activation of PKC in intact human platelets. 284 90

In response to phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA), HL-60 cells differentiate to macrophage-like cells and exhibit the ability to phosphorylate vinculin in vitro. Adriamycin-resistant HL-60 (HL-60/ADR) cells similarly demonstrate this characteristic without prior treatment with TPA. Since protein kinase C (PK-C) is a cellular TPA receptor, we have examined the role of this enzyme in the inherent ability of HL-60/ADR cells to phosphorylate vinculin. DEAE-cellulose chromatography of cell extracts revealed that HL-60/ADR cells contained 2-fold more PK-C than did the parental cell line. All PK-C activity was found in the cytosol of wild type HL-60 cells, whereas 85% of PK-C activity was cytosolic and 15% was membrane-bound in HL-60/ADR cells. After a 2-day treatment with 10 nM TPA, PK-C activity was reduced 80-90% in both cell lines regardless of its intracellular distribution. Immunoblotting of cell extracts from HL-60/ADR cells or HL-60 cells following treatment with TPA revealed increased levels of a 52-kDa species of similar mass to M-kinase. Coincident with these changes after TPA treatment was a reduction in Ca2+ and phospholipid-independent phosphorylation of vinculin in vitro in extracts from HL-60/ADR cells, whereas HL-60 cells exhibited an elevation of this phosphoprotein. The phosphorylation of vinculin in TPA-treated HL-60 cells or untreated HL-60/ADR cells was blocked by antibodies to protein kinase C. These results suggest that it is not the absolute level of protein kinase C but rather the proteolytic activation of PK-C to a Ca2+ and phospholipid-independent form which is associated with the utilization of vinculin as an endogenous substrate.
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PMID:Role of protein kinase C in phosphorylation of vinculin in adriamycin-resistant HL-60 leukemia cells. 313 Sep 82

One mechanism by which drugs alter the function of enzymes is through chronic inhibition. To determine whether commonly used cancer chemotherapeutic agents could alter protein kinase C (PKC) and thereby modify the calcium-messenger system, we studied the effect of anthracyclines and vinca alkaloids on the activity of PKC. Doxorubicin, daunomycin, vincristine and vinblastine inhibited the activity of PKC by 50% at concentrations of 150, 120, 350 and 140 microM respectively. Furthermore, we demonstrated the potential for this interaction to occur in intact cells, since doxorubicin blocked the binding of the phorbol ester, PDBu, to its receptor, PKC. The mode of inhibition of PKC was due, at least in part, to interference with the activation of the enzyme by phosphatidylserine. The activity of PKC was increased 15 fold in a highly resistant human breast cancer line, but this increase in enzymic activity was not seen in all lines tested. These studies demonstrate that anthracyclines and vinca alkaloids inhibit PKC, and suggest that chronic antagonism could lead to changes in its activity and function.
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PMID:Inhibition of protein kinase C by antineoplastic agents: implications for drug resistance. 368 68

Expression of P-glycoprotein by tumor cells confers resistance to multiple natural product drugs because of its ability to export these compounds. This transporter is a substrate for several protein kinases; however, the functional significance of its phosphorylation is not defined. We examined the effects of many activators and inhibitors of protein kinases on the activity of P-glycoprotein in drug-resistant human breast carcinoma cells (MCF-7/ADR). Several phorbol esters sensitized these cells to P-glycoprotein substrate drugs; however, there was no correlation with activation of protein kinase C. The 4 alpha- and 4 beta-isomers of phorbol 12-myristate 13-acetate were equally potent in sensitizing the cells to actinomycin D and daunomycin and in increasing the intracellular accumulation of [3H]vinblastine. These effects of 4 beta-phorbol myristate acetate required much higher concentrations than were needed to increase P-glycoprotein phosphorylation and were not antagonized by staurosporine. Similar to verapamil, the phorbol esters did not sensitize MCF-7/ADR cells to cisplatin, nor parental MCF-7 cells to any of the anticancer drugs. Mezerein, K-252a, and H-89 sensitized MCF-7/ADR cells, increased intracellular accumulation of [3H]vinblastine, and antagonized photolabeling of P-glycoprotein by [3H]azidopine. Therefore, phosphorylation does not appear to play a significant role in regulating P-glycoprotein activity in MCF-7/ADR cells.
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PMID:Circumvention of P-glycoprotein-mediated multiple drug resistance by phosphorylation modulators is independent of protein kinases. 749 4

We studied the effect of ionizing radiation on the activation of the AP-1 transcription factors and the regulation of basic fibroblast growth factor (bFGF) gene expression in drug-sensitive human breast carcinoma (MCF-7) cells and its drug-resistant variant (MCF-7/ADR) cells. Northern blot and gel mobility shift assays showed that 135 cGy of ionizing radiation induced c-jun and c-fos gene expression, AP-1 binding activity, as well as bFGF gene expression in MCF-7/ADR cells. In MCF-7 cells, however, we observed little/no induction of bFGF gene expression and AP-1 binding activity after the stress. Nevertheless, MCF-7 cells transfected with plasmids containing c-jun gene contain high levels of bFGF protein. H-7 (60 micrograms/ml), a potent protein kinase C (PKC) inhibitor, inhibited the stress-induced AP-1 binding activity and bFGF gene expression in MCF-7/ADR cells. Corroborating this observation, overexpression of PKC alpha induced bFGF gene expression in MCF-7 cells. Taken together, these results suggest that stress-induced bFGF gene expression is mediated through the activation of PKC and AP-1 transcription factors. Differences in the levels of PKC activity and AP-1 binding factors may be responsible for differential expression of bFGF among breast cancer cell lines. Although there are large differences in response to ionizing radiation between MCF-7 and MCF-7/ADR cell lines, we observed no significant differences in radiocytotoxicity between them.
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PMID:Effect of ionizing radiation on AP-1 binding activity and basic fibroblast growth factor gene expression in drug-sensitive human breast carcinoma MCF-7 and multidrug-resistant MCF-7/ADR cells. 749 2

Calphostin C is a potent and specific inhibitor of protein kinase C (PKC). In this investigation we examined the effect of Calphostin C (without prior exposure to light) on daunorubicin (DNR) accumulation and sensitivity to DNR in multidrug-resistant (MDR) murine leukemia P388/ADR and human myeloid leukemia HL60/AR cells. P388/ADR cells overexpress P-glycoprotein, whereas HL60/AR cells lack any expression of P-glycoprotein (both at mRNA and protein levels). Calphostin C, in a concentration-dependent manner, increased the accumulation of DNR in P388/ADR cells and partially reversed (threefold) the DNR resistance in P388/ADR cells but had no effect on either of the parameters in HL60/AR cells. Calphostin C-induced increased accumulation of DNR in P388/ADR cells was due to increased uptake and decreased efflux of DNR. Furthermore, Calphostin C increased the uptake and decreased the efflux of rhodamine 123 (a substrate for P-gp) in P388/ADR cells but had no such effect in P388 cells. In addition, Calphostin C without exposure to light did not inhibit PKC activity in any of the cell lines studied. Taken together, these data suggest that Calphostin C may reverse drug resistance via P-glycoprotein independently of its effect on PKC activity. Therefore, any data regarding the effect of Calphostin C on the reversal of MDR should be interpreted in the light of these findings.
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PMID:Effect of Calphostin C (PKC inhibitor) on daunorubicin resistance in P388/ADR and HL60/AR cells: reversal of drug resistance possibly via P-glycoprotein. 751 83

Cytoplasmic extracts from proliferating Neuro-2a cells contain a protein factor, ADR (activator of DNA replication) that induces DNA synthesis in isolated quiescent nuclei. Cytoplasmic extracts derived from quiescent-made Neuro-2a cells contain none or very little ADR activity, but this activity can be generated after a brief exposure of cytosolic extracts to a membrane-enriched fraction derived from exponentially growing Neuro-2a cells. ADR activity appears at the beginning of the S phase of the cell cycle. Moreover it appears to be a protease, because aprotinin inhibits ADR activity. ADR activity can be also inhibited by the protein kinase C inhibitors, 1-(5-isoquinoline-sulfonyl)-2- methylpiperazine (H7) and calphostin C.
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PMID:Protein kinase C inhibitors, H7 and calphostin C, inhibit induction of DNA synthesis by cytosolic extracts of exponentially growing neuroblastoma cells in isolated nuclei. 753 73

Basic fibroblast growth factor (bFGF) has been shown to be a potent mitogen and a promoter of angiogenesis. It has been hypothesized that the expression of the bFGF gene may be induced by stress of various types. To test that hypothesis, we investigated the expression of the bFGF gene during heat treatment in adriamycin-resistant (MCF-7/ADR) and -sensitive (MCF-7) human breast carcinoma cells. Under normal growth conditions, the bFGF mRNA was detected in MCF-7/ADR cells, while it was not detectable in MCF-7 cells by Northern blot analysis. During heating at 41 degrees C, the level of bFGF mRNA increased in MCF-7/ADR cells and the message became detectable in the MCF-7 cell line. However, after continuous heating at 41 degrees C for 24 h, the bFGF mRNA level decreased to control level in MCF-7/ADR cells. Interestingly, simultaneous treatment with heat and 60 micrograms/ml H-7 (1-(isoquinolinylsulfonyl)-2-methylpiperazine, a potent PKC inhibitor) decreased the level of bFGF mRNA in MCF-7/ADR cells. These results suggest that a protein kinase, likely PKC, is involved in the transcriptional regulation of the heat-enhanced bFGF gene expression in human breast carcinoma cells. Although no heat shock element can be identified in the promoter of the bFGF gene, we observed that the AP-1 binding activity to a TPA responsive element (TRE)-like sequence in the promoter of bFGF gene was enhanced by heat, as tested by mobility shift assay. Antibody developed against the c-Jun and c-Fos proteins inhibited the AP-1 binding activity to TRE. Therefore, the AP-1 complex appears to be responsible for the heat-enhanced binding to the TRE-like motif of the bFGF gene. Furthermore, the increased AP-1 binding activity does not require new protein synthesis but activation of the preexisting c-Jun proteins.
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PMID:Heat-induced bFGF gene expression in the absence of heat shock element correlates with enhanced AP-1 binding activity. 762 86

To define a role of protein kinase C (PKC) in multidrug resistance (MDR), we examined the influence of PKC isozyme specific antibodies delivered intracellularly, on drug sensitivity and drug accumulation in P388/ADR cells. Drug sensitive (P388) and drug resistant (P388/ADR) cells were permeabilized at 4 degrees C with L-lysolecithin and were incubated with rabbit anti-PKC, alpha, beta antibodies, or normal rabbit serum for 10 minutes at 37 degrees C. Daunorubicin (DNR) accumulation and drug sensitivity were studied by flow cytometry and MTT assay, respectively. Anti-PKC beta antibody partially corrected drug accumulation defect and completely reversed resistance to DNR. Anti-PKC alpha antibody had no effect on either parameter of MDR. These results suggest that PKC beta plays an important role in MDR in P388/ADR cells. Furthermore, the technique of intracellular delivery of antibodies provides a new approach to discern the role of PKC isoforms in multidrug resistance in various tumor cells.
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PMID:Role of protein kinase beta isozyme in multidrug resistance in murine leukemia P388/ADR cells. 766 24

The expression of protein kinase C (PKC) in 83 untreated solid human non-small cell lung carcinomas was determined and its correlation with inherent resistance to doxorubicin, with the expression of P-glycoprotein (P-170), and with the expression of glutathione S-transferase-pi (GST-pi) was analysed. Doxorubicin resistance was measured using an in vitro short-term test. The expression of PKC, P-170 and GST-pi was assessed immunohistochemically. Twenty-three tumors (= 28%) were PKC-positive, whereas 60 tumors (= 72%) were PKC-negative. Nineteen tumors (= 23%) were classified as sensitive and 64 tumors (= 77%) as resistant to doxorubicin. Thirty-nine tumors (= 47%) were P-170-positive and 51 tumors (= 61%) GST-pi-positive. Out of the PKC-positive tumors, 21 were resistant to doxorubicin and 2 were sensitive. Of the same 23 tumors, 18 were P-170-positive and 19 were GST-pi-positive. The correlations between the expression of PKC and the resistance to doxorubicin, the expression of P-170 and the expression of GST-pi were statistically significant. Corresponding results were obtained comparing the results of all tumors with the results of a subgroup of tumors having the same histology (squamous cell carcinomas). This supports the hypothesis that PKC is involved in the inherent doxorubicin-resistance of human lung cancer.
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PMID:Associated expression of protein kinase C with resistance to doxorubicin in human lung cancer. 776 22


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