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

Recently, we reported that low (PC-1)- and high-invasive cell lines (PC-1.0) were established on the basis of hamster pancreatic ductal adenocarcinomas, and PC-1.0 cells were secreting the dissociation factor in the supernatant (DF-CM) which induced cell dissociation and enhancement of cell motility. The cell motility of PC-1.0 is about 6 times as high as that of PC-1, which was continuously maintained in an autocrine fashion by DF-CM. In contrast, cell motility of PC-1 was rapidly induced by DF-CM with a high level of induction of endogenous c-fos mRNA and returned to a basal level within 6 h. The inhibition experiment using antisense oligonucleotides to c-fos indicated that the high level of induction of c-fos mRNA observed in the DF-CM-treated PC-1 cells was closely associated with their induction of cell motility. To elucidate these differences of responses against DF-CM between PC-1 and PC-1.0, signal transduction pathways of induction of the cell motilities were analyzed, using protein kinase C (PKC) inhibitor, 12-O-tetradecanoylphorbol-13-acetate, cyclic AMP antagonist, and cyclic AMP agonist. The transiently enhanced cell motility of DF-CM-treated PC-1 cells was completely inhibited by the cyclic AMP antagonist, and the cyclic AMP agonist was able to induce a similar pattern of induction of cell motility in PC-1 cells to DF-CM. On the other hand, the highly enhanced cell motility of PC-1.0 was completely inhibited by protein kinase C inhibitor, but not by cyclic AMP antagonist. These results suggest that cell motility of low-invasive PC-1 cells is under control through cyclic AMP-dependent protein kinase A, while the protein kinase C pathway seems favorable for high-invasive PC-1.0 cells to maintain the continuously enhanced cell motility responsible for their high invasiveness.
Invasion Metastasis 1997
PMID:Signal transduction pathway of the induction of cell motility in hamster pancreatic ductal adenocarcinoma cell. 942 21

The prototype of a new class of antiproliferative phospholipid analogs, hexadecylphosphocholine (HePC), has been shown to inhibit tumor growth and is currently used for the treatment of cutaneous metastases of mammary carcinomas. Although several cellular targets of HePC, e.g. protein kinase C and CTP:phosphocholine cytidylyltransferase, have been proposed, the mechanisms of HePC-induced anticancer activity are still unclear. Considering that the antiproliferative effect of HePC correlates with inhibition of phosphatidylcholine biosynthesis, which is tightly coupled to sphingomyelin biosynthesis, we tested the hypothesis that treatment of cells with the anticancer drug leads to increased cellular ceramide and subsequently to apoptotic cell death. In the present study, we showed that 25 micromol/liter HePC induced apoptosis. In further experiments, we demonstrated that HePC inhibited the incorporation of radiolabeled choline into phosphatidylcholine and at a later time point into sphingomyelin. This was confirmed by metabolic labeling of the lipid backbone using radiolabeled serine, and it was shown that HePC decreased the incorporation of serine into sphingomyelin by 35% and simultaneously increased the incorporation of serine into ceramide by 70%. Determination of the amount of ceramide revealed an increase of 53% in HePC-treated cells compared with controls. In accordance with the hypothesis that elevated ceramide levels may be the missing link between the metabolic effects of HePC and its proapoptotic properties, HePC-induced apoptosis was blocked by fumonisin B1, an inhibitor of ceramide synthesis. Furthermore, we found that membrane-permeable ceramides additively increased the apoptotic effect of HePC.
 ...
PMID:Induction of ceramide-mediated apoptosis by the anticancer phospholipid analog, hexadecylphosphocholine. 955 84

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.
 ...
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.
 ...
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

Using a pure chemotactic model, we investigated the effect of plasmin on tumor cell motility. In the presence of various extracellular matrix proteins, plasmin facilitated motility of human melanoma LOX and lung cancer Lu-99 cells. Laminin contributed most to the action of plasmin. The cell motility induced by plasmin and laminin was chemokinetic in nature and was almost completely suppressed by alpha2-antiplasmin. To further characterize the action of plasmin, various signal transduction kinase inhibitors were tried out. The results suggested that plasmin may modulate cell motility through protein kinase C and mitogen-activated protein kinase cascades in cooperation with laminin.
Invasion Metastasis 1997
PMID:Modulation of tumor cell motility by plasmin. 994 91

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

Metastasis requires cytoskeletal remodeling for migration, adhesion, and extravasation of metastatic cells. Although protein kinase C (PKC) is involved in tumor promotion/progression and cytoskeletal remodeling, its role in metastasis has not been defined. PKCdelta levels are increased in highly metastatic 13762NF mammary tumor cells (MTLn3) compared with less metastatic, parental cell lines. To determine whether the increase in endogenous PKCdelta is functionally related to their increased metastatic potential, we prepared MTLn3 cells that express the inhibitory regulatory domain fragment of PKCdelta (RDdelta) under the control of a tetracycline-inducible promoter. RDdelta expression attenuated endogenous PKCdelta activity, as demonstrated by decreased phosphorylation of the PKCdelta substrate adducin in migrating cells. Thus, in MT cells, RDdelta appears to primarily influence cytoskeleton-dependent processes rather than cell cycle progression. To determine whether RDdelta expression influenced metastatic potential in vivo, MTLn3/RDdelta cells were either grown in the mammary fat pad or injected into the tail vein of syngeneic rats, and effects of doxycycline-induced RDdelta expression on pulmonary metastases were studied. Consistent with the in vitro data, induction of RDdelta significantly reduced the number of lung metastases without affecting growth of the primary tumor. These results suggest that interfering with endogenous PKCdelta activity by expressing the inhibitory RDdelta fragment inhibits cytoskeleton-regulated processes important for MTLn3 cell metastasis.
 ...
PMID:Protein kinase C delta involvement in mammary tumor cell metastasis. 1039 70

We previously found that 12-O-tetradecanoylphorbol-13-acetate (TPA)-enhanced invasiveness was associated with augmentation of cell motility but not that of metalloproteinase activity in a highly metastatic variant (L-10) of the human colon adenocarcinoma cell line RCM-1 and that this enhancement was possibly mediated by protein kinase C (PKC). In this study, we first intended to determine the specific isoforms of PKC involved in this TPA-enhanced L-10 cell motility that leads to invasion, and then investigated the way to inhibit the enhanced motility and invasion by using antisense oligodeoxynucleotides (ODN) targeting the isoform. An activator of conventional PKC isoforms (cPKC), thymeleatoxin, enhanced L-10 cell motility and invasion like TPA, and an inhibitor of cPKC, Go-6976, efficiently inhibited TPA-enhanced motility and invasion. TPA treatment induced a shift of PKC-alpha, but not other isoforms, from the cytosol to the membrane fraction, indicating the activation of the isoform. During the assay period, only activation but not downregulation of PKC-alpha occurred with the low concentration of TPA used in our assays. Antisense ODNs specific for PKC-alpha efficiently reduced its expression at the protein levels and inhibited L-10 cell motility in the absence of TPA. With TPA treatment, however, the remaining PKC-alpha was sufficient for activation leading to enhanced invasion. Only a combination of depletion of PKC by prolonged stimulation with a high concentration of phorbol 12,13 dibutyrate (PDBu) and treatment with antisense ODNs effectively inhibited L-10 cell invasion even in the presence of TPA. These results suggested that downregulation of PKC isoforms by treatment with antisense ODNs alone is insufficient to suppress the isoform-mediated cellular events in the presence of PKC activators, and thus that some additional treatments are necessary for the successful downregulation of them.
Clin Exp Metastasis 1999 Jun
PMID:TPA-enhanced motility and invasion in a highly metastatic variant (L-10) of human rectal adenocarcinoma cell line RCM-1: selective role of PKC-alpha and its inhibition by a combination of PDBu-induced PKC downregulation and antisense oligonucleotides treatment. 1054 22

Angiogenesis is required for tumor formation and growth; inhibition of angiogenesis is a promising new approach in cancer therapy. UCN-01, a protein kinase C (PKC) inhibitor, induces growth arrest and apoptosis in cancer cells and was recently introduced in a phase I clinical trial. We demonstrate that UCN-01, at concentrations lower than those necessary to inhibit cancer cell growth, inhibit proliferation of human endothelial cells in vitro. Moreover, UCN-01, at concentrations as low as 32 nM, prevent microvessel outgrowth from explant cultures of rat aortic rings. Since hypoxia activates hypoxia-inducible factor (HIF-1)-dependent transcription in cancer cells that, in a paracrine fashion, drive tumor angiogenesis, we investigated the effects of UCN-01 on HIF-1-responsive promoter constructs. We report that, in addition to direct inhibitory effects on endothelial cell growth, UCN-01 abrogates hypoxia-mediated transactivation of HIF-1-responsive promoters in a prostate cancer cell line. We conclude that UCN-01, at clinically relevant concentrations, exerts an anti-neovascularization effect by blocking two important steps in vessel formation: (1) the response of cancer cells to hypoxia, and (2) endothelial cell proliferation.
Invasion Metastasis
PMID:UCN-01, a protein kinase C inhibitor, inhibits endothelial cell proliferation and angiogenic hypoxic response. 1064 Sep 7

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


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>