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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that the Ca(2+)- and phospholipid-dependent protein kinase, protein kinase C (PKC), was involved in rat Walker carcinosarcoma cell adhesion to large-vessel endothelium. We extended our studies to explore the role of this kinase in the adhesion to small-vessel endothelium and lung colonization of murine B16 amelanotic melanoma (B16a). Subpopulations of B16a cells, which differ in lung-colonization potentials, were isolated by centrifugal elutriation from solid tumors. In this study, we demonstrate that cells from a high metastatic sub-population (HM340), when compared with cells from a low metastatic sub-population (LM180), exhibit elevated levels of total cellular as well as membrane-bound PKC. The increase in PKC in cells from the HM340 correlates positively to their increased ability to adhere to murine pulmonary-microvessel endothelial-cell monolayer, and to form pulmonary colonies in syngeneic mice. Calphostin C, a potent and selective PKC inhibitor, decreases in a dose-dependent manner the adhesion to endothelium and the lung colonization of cells from both the low and the high metastatic sub-populations with IC50 at sub-micromolar concentrations. In conclusion, our results suggest that PKC may be a key element in regulating tumor-cell metastasis and that PKC inhibitors may be anti-metastatic agents.
...
PMID:Protein-kinase-C inhibitor calphostin C reduces B16 amelanotic melanoma cell adhesion to endothelium and lung colonization. 137 95

The structure/activity relationship of the protein kinase inhibitors, staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (ID50 of about 6.0 x 10(-8) M) as well as spontaneous and colchicine-stimulated locomotion at 10(-7) M. K 252a suppresses cell polarity (ID50 of about 4.5 x 10(-6) M) and inhibits spontaneous and colchicine-stimulated locomotion at 10(-5) M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a staurosporine derivative with a much higher specificity for protein kinase C (PKC) than staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotide-dependent protein kinases, and CGP 42700, an inactive staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.
...
PMID:Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells. 145 47

The hepatic cyclic nucleotide system and hepatic monooxygenase activity were examined in male rats following intramuscular or subcutaneous Walker 256 carcinosarcoma transplantation. Twelve days of continuous s.c. tumor growth significantly increased hepatic cyclic AMP levels, while levels of cyclic GMP, cytochrome P-450, cytochrome b-5, and p-chloro-N-methylaniline metabolism were significantly decreased. Whole blood from 6 day i.m. tumor-bearing rats incubated with liver slices obtained from non-tumor-bearing rats produced significantly elevated hepatic cyclic AMP levels concurrent with significantly depressed hepatic p-chloro-N-methylaniline metabolism. The chronological monitoring of tumor growth demonstrated a close temporal relationship between decreased cyclic AMP-dependent protein kinase activity, microsomal metabolism of p-chloro-N-methylaniline, and the mixed-function oxidase system. Significant changes in these hepatic enzyme systems occurred as early as 17 hours following tumor transplantation. At this same time, sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed the appearance of a 184,000 molecular weight protein in hepatic tissue from all tumor-bearing rats. These studies are compatible with the proposal that the hepatic cyclic AMP system may modulate toxohormone effects on hepatic drug biotransformation.
...
PMID:The relationship of the cyclic nucleotide system to inhibition of hepatic drug metabolism in Walker 256 carcinoma-bearing rats. 625 21

We have investigated the regulatory role of PGI2 and its stable analogs, i.e., iloprost and cicaprost, on 12(S)-HETE- and TPA-enhanced tumor cell integrin expression and adhesion. Walker 256 carcinosarcoma cells express alpha IIb beta 3 integrin receptors, which mediate their adhesion to endothelium, subendothelial matrix and fibronectin. Adhesion is enhanced by treatment with exogenous 12(S)-HETE but not 12(R)-HETE or other lipoxygenase-derived hydroxy fatty acids, as well as by TPA. Both 12(S)-HETE and TPA enhanced alpha IIb beta 3 expression on W256 cells. PGI2 iloprost and cicaprost inhibited both 12(S)-HETE- and TPA-enhanced adhesion to endothelium and subendothelial matrix as well as alpha IIb beta 3 expression on W256 cells. The mechanism responsible for the effect of PGI2 was explored. Prostacyclin treatment of W256 cells resulted in an enhanced production of cAMP in a time- and dose-dependent manner. Pre-treatment of tumor cells with increasing concentrations of adenosine resulted in a dose-dependent decrease in the PGI2 effect on TPA or 12(S)-HETE-enhanced adhesion, suggesting that the PGI2 effect is mediated through PKA. Dibutyryl cAMP also blocked the 12(S)-HETE- or TPA-enhanced adhesion, and adenosine pre-treatment did not result in an inhibition of the dibutyryl cAMP effect. Collectively, our results suggest that the cyclooxygenase metabolite PGI2 can antagonize the lipoxygenase metabolite 12(S)-HETE- and TPA-enhanced alpha IIb beta 3 expression and tumor cell adhesion via activation of adenylate cyclase and elevation of intracellular levels of cAMP.
...
PMID:Inhibition of TPA and 12(S)-HETE-stimulated tumor cell adhesion by prostacyclin and its stable analogs: rationale for their antimetastatic effects. 753 Feb 35

Previous work has shown that PMA and diacylglycerols, activators of protein kinase C (PKC) can suppress cell polarity and locomotor activity of Walker carcinosarcoma cells in vitro, suggesting that PKC activation may result in a stop signal for tumor cell locomotion. This hypothesis was further analysed. The present results show that the DAG kinase inhibitor, R 59022, suppressed tumor cell polarity and strongly inhibited cell locomotion at a concentration of 10(-4), thus supporting the earlier finding that an increased availability of DAGs can suppress the locomotor activity of Walker carcinosarcoma cells. The results support the stop-signal hypothesis of PKC activation insofar as DAG kinase inhibition mimics the effects of DAGs and PMA. In order to clarify further the effects of protein kinase modulation on locomotion, we now extended our studies on structurally different inhibitors of protein kinases. In contrast to H-7, HA-1004 had no effect on cell polarity and did not reduce cell locomotion in the presence of colchicine, but reduced the proportion of spontaneously locomoting cells by 70% at 3 x 10(-4) M. Polymyxin B suppressed cell polarity and locomotion only at concentrations that proved to be toxic. Tamoxifen had no significant effect on cell polarity and locomotor activity. Sangivamycin did not suppress cell polarity and spontaneous locomotion at a concentration range of 10(-9) M to 10(-4) M. However, at 10(-4) M it decreased the proportion of migrating, colchicine-stimulated cells by 50%. The diverse responses to structurally different PKC inhibitors may be explained by their limited and variable specificity for PKC and different mechanisms of action on PKC.
...
PMID:Shape changes and chemokinesis of Walker carcinosarcoma cells: effects of protein kinase inhibitors (HA-1004, polymyxin B, sangivamycin and tamoxifen) and an inhibitor of diacylglycerol kinase (R 59022). 839 Aug 1

Endometrial carcinosarcomas are aggressive neoplasias composed of high-grade carcinomatous and sarcomatous elements. The pathogenesis and specific genetic alterations underlying these tumors are still not well known. We analyzed alterations in oncogenes involved in the pathogenesis of endometrial carcinomas that might represent predictive markers for specific therapies. Immunohistochemistry for HER2 (tyrosine kinase-type cell surface receptor HER2) and c-KIT (tyrosine-protein kinase Kit) and fluorescence in situ hybridization for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma receptor tyrosine kinase) were carried out for 76 endometrial carcinosarcoma samples on sequential tissue microarray sections. Analysis of 238 mutations across 19 common oncogenes was performed on 34 samples using the Sequenom OncoCarta Panel (Sequenom, Hamburg, Germany). We observed EGFR, HER2, and c-KIT expression in 71%, 1.5%, and 2.7% of tumors, respectively. EGFR amplification was detected in 11 of 76 endometrial carcinosarcomas (14.5%). Four samples showed both amplification and aneuploidy (5.2%). ALK amplification together with chromosome 2 polysomy was found in 1.3% of endometrial carcinosarcomas. In total, 23 mutations in 9 different oncogenes were detected in 15 (44.1%) of 34 endometrial carcinosarcomas. Five endometrial carcinosarcomas (14.7%) had 2 or more mutations. Eleven tumors (32.3%) had mutations affecting the PI3K (phosphoinositide-3-kinase)/AKT (v-akt murine thymoma viral oncogene homolog 1) (6 mutations in PIK3CA (PI3K catalytic alpha polypeptide) and 1 in AKT) and/or RAS/BRAF (serine/threonine-protein kinase B-raf) pathway (3 KRAS [kirsten RAS oncogene homolog], 2 NRAS [neuroblastoma RAS viral oncogene homolog], and 1 BRAF). Mutations in PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) and/or KIT were found in 5 endometrial carcinosarcomas (14.7%). Finally, we found mutations in MET (met proto-oncogene [hepatocyte growth factor receptor]) in 2 tumors (5.9%) and in EGFR in one (2.9%). Our study evidences mutations in oncogenes in endometrial carcinosarcomas that are targets or modulators of response to specific therapies in other human cancers, with PI3K/AKT being the most frequently altered pathway.
...
PMID:Oncogene alterations in endometrial carcinosarcomas. 2319 29

---