Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) is composed of a family of isozymes that transduce signals of certain hormones, growth factors, lectins, and neurotransmitters. This review addresses the role of PKC in the regulation of cellular proliferation and its disorders. PKC is directly activated in vivo by the second messenger diacylglycerol, a lipid produced by phospholipase C-catalyzed hydrolysis of phosphatidylinositol and polyphosphoinositides. Diacylglycerol activates PKC by reducing the enzyme's requirement for Ca2+. Phorbol ester tumor promoters and related agents potently activate PKC by a mechanism analogous to that of diacylglycerol, providing evidence that PKC activation is a critical event in tumor promotion. However, the role of PKC activation in tumor promotion is not entirely clear. For example, bryostatin is a potent PKC activator that antagonizes phorbol ester-mediated tumor promotion, and mezerein is a second-stage tumor promoter that potently activates PKC. In addition to studies concerned with tumor promotion, studies of oncogene action also indicate a role for PKC in carcinogenesis. A number of plasma membrane-associated oncogene products and related proteins are PKC substrates, and PKC activation leads to induction of the expression of oncogenes that code for nuclear proteins. PKC is implicated in human breast and colon carcinogenesis. Tumor-promoting bile acids activate PKC, and PKC expression studies in rat colonic epithelial cells and human breast cancer cells indicate a positive role for PKC in the proliferation of the cells. Altered expression of PKC in human colon and breast tumors indicates that PKC isozymes may be useful markers for these diseases.
Cancer Metastasis Rev 1989 Dec
PMID:Biology of the protein kinase C family. 269 70

Protein kinase C (PKC) is a family of closely related lipid-dependent and diacyglycerol-activated isoenzymes known to play an important role in the signal transduction pathways involved in hormone release, mitogenesis and tumor promotion. Reversible activation of PKC by the second messengers diacylglycerol and calcium is an established model for the short term regulation of PKC in the immediate events of signal transduction. PKC can also be modulated long term by changes in the levels of activators or inhibitors for a prolonged period or by changes in the levels of functional PKC isoenzymes in the cell during development or in response to hormones and/or differentiation factors. Indeed, studies have indicated that the sustained activation or inhibition of PKC activity in vivo may play a critical role in regulation of long term cellular events such as proliferation, differentiation and tumorigenesis. In addition, these regulatory events are important in colon cancer, where a decrease in PKC activators and activity suggests PKC acts as an anti-oncogene, in breast cancer, where an increase in PKC activity suggests an oncogenic role for PKC, and in multidrug resistance (MDR) and metastasis where an increase in PKC activity correlates with increased resistance and metastatic potential. These studies highlight the importance and significance of regulation of PKC activity in vivo.
Cancer Metastasis Rev 1994 Dec
PMID:Regulation of protein kinase C and role in cancer biology. 771 99

The biological behavior of osteosarcoma in dogs is similar to that in humans and the dog has been suggested as a model for the disease in humans. Because occult metastatic disease is common at presentation, systemic therapy is necessary. The dihydropyridine, dexniguldipine hydrochloride (B859-35), is a potent inhibitor of protein-kinase-C(PKC)-stimulated cell proliferation and has shown therapeutic activity in experimentally induced neuroendocrine hamster lung tumors and in a mammary cancer cell line. In human osteosarcoma cell lines, PKC activity can be down-regulated, resulting in increased sensitivity to cisplatin. Since these results supported the involvement of PKC inhibitors in the therapeutic management of osteosarcoma, we performed a prospective, randomized clinical trial using dogs with naturally occurring appendicular osteosarcoma to determine the therapeutic potential of dexniguldipine. Dogs received either no drug treatment (control group, n = 8), standard treatment (e.g., cisplatin, n = 14), or dexniguldipine treatment (n = 14) following amputation. Dexniguldipine- and cisplatin-treated dogs had a longer median remission duration and survival time than untreated dogs (P < 0.05); however, dexniguldipine-treated dogs had a shorter survival time than cisplatin-treated dogs (P < 0.05). The results of this study demonstrate that dexniguldipine has significant activity in the inhibition of canine osteosarcoma micrometastases. The identification of a tumor model that may be responsive to this class of antiproliferative agents warrants further clinical investigation to determine the optimum dosage of dexniguldipine and the role it may have in the therapeutic management of canine osteosarcoma.
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PMID:Amputation and dexniguldipine as treatment for canine appendicular osteosarcoma. 899 38

PKC, a family of 11 related isoforms, appears deeply implicated in carcinogenesis and in the metastatic process, however, little being known on the specific role of each isoform in that process. In this work we analysed the subcellular distribution and the in situ expression of classical PKC (alpha and beta) isoforms and the expression of PKC delta in the tumour and lung-metastases induced in the rat using the 'resistant hepatocyte' model of diethylnitrosamine-induced hepatocarcinogenesis. With respect to control untreated liver, an activation and increased expression of PKC alpha was observed in tumour and lung metastatic nodules, while cytosolic and membrane PKC beta was undetectable. In contrast, nuclear PKC beta showed an increased activity in the tumour and a marked increased activity and expression in metastatic nodules, suggesting a possible role of such isoform in the metastatic process. The analysis of PKC delta expression revealed a down regulation in both tissues with respect to control untreated liver, suggesting the inhibitory role of such isoform on tumour cell proliferation in agreement with our previous observations. Taken together, these results point to a different role for PKC alpha and delta in the development of tumour and metastatic nodules using the 'resistant hepatocyte' model of liver carcinogenesis, and suggest a possible involvement of nuclear PKC beta in the development of secondary tumours.
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PMID:Changes in protein kinase C alpha, delta and in nuclear beta isoform expression in tumour and lung metastatic nodules induced by diethylnitrosamine in the rat. 911 Dec 5

To determine whether alteration of PKC alpha expression would affect the metastatic potential of human melanoma cells, replicate cultures of C8161 cells were treated in vitro with a phosphorothioate antisense oligodeoxynucleotide (ODN) that specifically inhibits PKC alpha expression (ISIS-3521). Control C8161 cultures were treated with a scrambled sequence ODN, cationic liposomes or were left untreated. Northern blots demonstrated 70% inhibition of PKC alpha mRNA in ISIS-3521-treated cells compared to controls. Metastasis was suppressed by 75% when ISIS-3521-treated cells were injected intravenously into athymic mice. These results show that PKC alpha expression is important in the regulation of human melanoma metastasis.
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PMID:Human melanoma metastasis is inhibited following ex vivo treatment with an antisense oligonucleotide to protein kinase C-alpha. 965 94

We have evaluated the effects of bryostatin 1 on growth of a highly malignant p53-null mouse mammary tumor line, 4T1, and the mechanism by which bryostatin 1 inhibits in vitro growth and in vivo development of tumor and metastases from the orthotopic site. Bryostatin 1 at 20-400 nM concentrations inhibits growth of 4T1 cells by approximately 60% in two-day cultures. Inhibition of growth is associated with an increase in the number of cells undergoing apoptosis with concomitant elevation in the steady state levels of bax protein and drop in bcl-2 levels. The cytotoxic effect of bryostatin 1 on 4T1 cells occurs independently of p53, since there was no evidence of p53-mediated transcriptional activity in 4T1 cells following treatment with bryostatin 1.4T1 cells respond in vivo to bryostatin 1 therapy (75 microg/kg body weight). Intraperitoneal administration of bryostatin 1 inhibits both primary and secondary tumor growth by approximately 50%. However, although bryostatin 1 has a remarkable capacity to slow tumor growth and progression, it is unable to completely eradicate tumor growth and progression due to in vivo development of tumor resistance to bryostatin 1. Levels and cellular distribution of PKCalpha and delta do not correlate with the growth inhibitory effects of bryostatin 1 on 4T1 cells; however, reduction in cytosolic PKCalpha and delta without associated increase in membrane compartment appear to correlate with bryostatin-resistance. Our results suggest that the therapeutic effects of bryostatin 1 in our system do not involve alterations in levels and distribution of PKC but rather a direct upregulation of bax/ bcl-2 ratios that is independent of p53.
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PMID:p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity. 985 25

In resting platelets integrin alphaIIbbeta3 is constitutively expressed in an inactive state and it does not recognize soluble proteins. Platelet activation results in a conformational change of the low-affinity alphaIIbbeta3 to a high-affinity state which then recognizes plasma fibrinogen. The ectopic expression of alphaIIbbeta3 integrin in rodent and human cells derived from solid tumors is well documented, although little is known about its affinity state in these tumor cells. In this study we analysed expression and function of high-affinity alphaIIbbeta3 in murine metastatic melanoma B16a cells by using a mAb that specifically recognizes high-affinity alphaIIbbeta3 (PAC-1). These tumor cells while in suspension bound PAC-1 and fibrinogen. Immunofluorescent studies of B16a cells indicated that high-affinity alphaIIbbeta3 is associated with the Golgi complex and the cell surface. Stimulation of B16a cells with a PKC-activator, 12(S)-HETE, induced translocation of the high-affinity integrin from an intracellular pool to the plasma membrane, which resulted in increased tumor cell adhesion to fibronectin. In addition to participating in 12(S)-HETE-stimulated adhesion of B16a cells, the high-affinity alphaIIbbeta3 integrin is also involved in tumor cell invasion through a reconstituted basement membrane. In conclusion, results from this study suggest that in non-megakaryocytic lineage B16a cells alphaIIbbeta3 is constitutively expressed in a high-affinity state, and that this conformation participates in tumor cell adhesion and invasion.
Clin Exp Metastasis 1998 Jul
PMID:Expression and function of the high affinity alphaIIbbeta3 integrin in murine melanoma cells. 1009 39

To resist substantial wall shear stress exerted by blood flow metastasizing colon carcinoma cells have to form adhesive contacts with endothelial cells and subendothelial extracellular matrix (ECM). At secondary sites tumor cells have to stabilize these initial adhesive interactions to prevent detachment and recirculation. Previously we found that adhesion of colon carcinoma cells to ECM components under static conditions is mediated, in part, by various beta1-integrins. Since other malignant cells possess adhesive properties that are different under static and dynamic conditions, we analyzed human colon carcinoma cell adhesion under flow by decreasing the flow (wall shear stress, WSS) of cell suspensions and allowing cells to interact with collagen-coated surfaces in a laminar flow chamber. HT-29 colon carcinoma cells were used to study wall shear adhesion threshold (WSAT), dynamic adhesion rate (DAR) and adhesion stabilization rate (ASR). DAR was determined after a low flow period using a WSS set at 50% of WSAT. ASR was calculated 60 sec after reestablishment of high WSS. Glass slides were coated with collagen I (C I) or bovine serum albumin (BSA, negative control). In some experiments cells were pretreated with function-blocking anti-beta1 or nonspecific IgG. Rolling of cells occurred on C I- and BSA-coated surfaces at high WSS. By decreasing WSS cell sticking without definite adhesion was found, and cells stuck to BSA at WSS lower than that found for C I. Further decreasing WSS below WSAT enabled stable cell adhesion to C I, but only a few cells adhered to BSA. ASR was found to be 73% of primarily adherent cells (to C I). Pretreatment with anti-beta1 did not affect cell rolling but did inhibit cell sticking and adhesion completely, whereas nonspecific IgG was without effect. Activation of PKC using phorbol ester resulted in an increase of adhesive interactions under dynamic and static conditions, whereas its inhibition reduced adhesion. Adhesive interactions of HT-29 colon carcinoma cells with ECM-coated surfaces under laminar flow conditions occurred in various steps: (1) rolling, (2) sticking or initial adhesion, and (3) stabilization of adhesion. Under shear flow rolling of tumor cells on ECM-coated surfaces appeared to be mediated mainly by physical/mechanical and nonspecific surface-cell membrane interactions, whereas stabilized adhesion to ECM was specifically mediated by beta1-integrin binding to ECM components. PKC seems to be involved in the regulation of adhesion stabilization under static and flow conditions.
Clin Exp Metastasis 1999 Jul
PMID:Beta1-integrin-mediated dynamic adhesion of colon carcinoma cells to extracellular matrix under laminar flow. 1065 4

The carbohydrate antigen sialyl-Lewis(a) is important to pancreatic tumour biology because the circulating antigen is used in serological tests for malignancy and because cell surface antigen is involved in tumour cell binding to the endothelial adhesion molecule, E-selectin, in extravasation. In this study, we examined the effects of the adenylyl cyclase activator, forskolin, and the diacylglycerol analogue, phorbol 12-myristate 13-acetate (PMA), on the expression and release of sialyl-Lewis(a) in human pancreatic cancer cells. Increases in the release of sialyl-Lewis(a) from SW1990 cells produced by forskolin and PMA were associated with increases in the activities of protein kinases A and C, respectively, and could be blocked by inhibitors specific for these enzymes. Immunoprecipitation experiments showed that sialyl-Lewis(a) was associated with MUC1 mucin. Forskolin also increased the cellular content of antigen and MUC1 mRNA. Actinomycin D and a protein kinase A inhibitor, H8, blocked these effects. In contrast, PMA reduced cellular antigen and MUC1 mRNA levels, although it produced a temporary increase in release of the antigen. The effects of PMA were blocked by the protein kinase C inhibitor, H7. PMA also reduced cell binding to the adhesion molecule E-selectin. In summary, PKA and PKC alter cell MUC1-associated sialyl-Lewis(a) in opposite directions. These changes may have clinical utility in the diagnosis of pancreatic cancer and the prevention of metastases.
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PMID:Forskolin and phorbol ester have opposite effects on the expression of mucin-associated sialyl-Lewis(a) in pancreatic cancer cells. 1074 4

Autocrine motility factor (AMF) is one of the motility cytokines regulating tumor cell migration, therefore identification of the signaling pathway coupled with it has critical importance. Previous studies revealed several elements of this pathway predominated by lipoxygenase-PKC activations but the role for tyrosine kinases remained questionable. Motility cytokines frequently have mitogenic effect as well, producing activation of overlapping signaling pathways therefore we have used B16a melanoma cells as models where AMF has exclusive motility effect. Our studies revealed that in B16a cells AMF initiated rapid (1-5 min) activation of the protein tyrosine kinase (PTK) cascade inducing phosphorylation of 179, 125, 95 and 40/37 kD proteins which was mediated by upstream cyclo- and lipoxygenases. The phosphorylated proteins were localized to the cortical actin-stress fiber attachment zones in situ by confocal microscopy. On the other hand, AMF receptor activation induced significant decrease in overall serine-phosphorylation level of cellular proteins accompanied by serine phosphorylation of 200, 90, 78 and 65 kd proteins. The decrease in serine phosphorylation was independent of PTKs, PKC as well as cyclo- and lipoxygenases. However, AMF induced robust translocation of PKCalpha to the stress fibers and cortical actin suggesting a critical role for this kinase in the generation of the motility signal. Based on the significant decrease in serine phosphorylation after AMF stimulus in B16a cells we postulated the involvement of putative serine/threonine phosphatase(s) upstream lipoxygenase and activation of the protein tyrosine kinase cascade downstream cyclo- and lipoxygenase(s) in the previously identified autocrine motility signal.
Clin Exp Metastasis 1999
PMID:Autocrine motility factor (neuroleukin, phosphohexose isomerase) induces cell movement through 12-lipoxygenase-dependent tyrosine phosphorylation and serine dephosphorylation events. 1108 78


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