Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanoma growth stimulatory activity factor (MGSA) is a polypeptide which was initially isolated from Hs294 human melanoma cells. Its sequence is identical to the deduced amino acid sequence of the human gro cDNA, isolated from a human tumor cell line. MGSA stimulates the proliferation of malignant melanoma cells, but its function for normal cells has not been defined. Here we report that human umbilical vein endothelial cells are capable of synthesizing and secreting MGSA. The expression and secretion of MGSA are strongly induced by factors often involved in inflammation such as IL-1, TNF, LPS and thrombin. The induction of MGSA mRNA is dose and time dependent and is independent of new protein synthesis. This stimulation could be mimicked by TPA, suggesting that the action could be mediated through activation of protein kinase C. Furthermore, addition of MGSA to the endothelial cell cultures induces gro/MGSA gene expression, implying that an autocrine mechanism exists. Our data suggest that the protein encoded by gro/MGSA mRNA may play a role in inflammation and exert its effects on endothelial cells in an autocrine fashion.
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PMID:Expression and secretion of gro/MGSA by stimulated human endothelial cells. 267 May 60

Retinoic acid inhibits the proliferation of B16 mouse melanoma cells. It also eliminates the ability of these cells to grow in soft agar. These biological actions of retinoic acid have been shown to be accompanied by an increase in the amount of cyclic AMP-dependent protein kinase and an induction of a new isozyme form (RII beta). In this report we demonstrated that retinoic acid-treated B16 melanoma cells had large increases in protein kinase C activity. This increased enzyme activity was accompanied by increases in both the number of phorbol dibutyrate binding sites and the amount of immunoreactive protein kinase C. Other treatments (melanocyte-stimulating hormone, serum deprivation) which inhibited the growth of these cells did not increase protein kinase C activity. When B16 melanoma cells were treated for a prolonged time (72 h) with phorbol dibutyrate, protein kinase C activity was barely detectable. Under these conditions, melanin production was inhibited and cell growth was accelerated. When retinoic acid was added together with phorbol dibutyrate, it prevented the growth stimulatory effect of the phorbol ester and increased protein kinase C activity. However, the absolute activity of the enzyme was still below that found in control cells and very much lower than in cells treated with retinoic acid alone. Taken together with our previous findings, we propose that the increase in protein kinase C might be part of a differentiation program induced by retinoic acid.
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PMID:Induction of protein kinase C in mouse melanoma cells by retinoic acid. 274 37

A correlative study was done to determine possible relationships between nonrandom aberrations in chromosomes 1, 6, and 7 occurring in human cutaneous malignant melanoma and the structure of oncogenes as well as specific genes encoding growth factors and growth factor receptors. Thirty cell lines derived from primary or metastatic melanomas of 28 patients were analyzed by Southern blotting with nick-translated probes for 28 different genes, some of which map near frequent chromosomal breakpoints observed in melanoma. An alteration in the MYB protooncogene was observed in a cell line derived from a primary melanoma in the vertical growth phase, which correlated with a 6q22 chromosomal abnormality. Another primary melanoma cell line had a cytogenetically undetected tumor-specific deletion within the gene for alpha-type protein kinase C. Polymorphic alleles for the genes encoding the epidermal growth factor receptor and alpha-type protein kinase C were also observed.
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PMID:Structural alteration in the MYB protooncogene and deletion within the gene encoding alpha-type protein kinase C in human melanoma cell lines. 282 78

We show that Cloudman melanoma cells undergo rapid arborization in response to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone, a potent analogue of alpha-melanocyte stimulating hormone (alpha-MSH). The arbors were established by extension of processes and resembled dendrites. We used this system to study the regulation of cell shape. alpha-MSH is known to induce increases in cAMP levels, and agents such as forskolin and isobutylmethylxanthine that led to increased cAMP also caused arborization. However, equally dramatic arbors were formed after incubation with the protein kinase C inhibitor H-7 [1-(5-isoquinolinesulfonyl)-alpha-methyl-piperazine]. Phorbol diesters that activate protein kinase C led to cell rounding and antagonized alpha-MSH. The actions of protein kinase C cannot be rationalized in terms of indirect effects on cAMP: neither H-7 nor phorbol diesters alone altered cAMP levels, nor did they affect the increase in cAMP induced by MSH. We show also that MSH produced longer-term effects that cannot be mimicked by cAMP. Specifically, even in the continued presence of alpha-MSH, arborization was followed by morphological reversal to the unstimulated flattened configuration within 2 hr. (This did not occur with other agents that increase cAMP or with H-7.) Most importantly, whereas MSH-induced arborization occurred in the presence of cycloheximide, actinomycin D, or in enucleated cells, the reversal of arborization did not. Thus, MSH induced a program of rapid shape change that was dependent on new protein synthesis and gene transcription.
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PMID:Regulation of cell shape in the Cloudman melanoma cell line. 303 40

Phospholipid-sensitive, Ca++-dependent protein kinase activity was investigated in the cytosol of melanoma cells. A protein kinase system was partially purified, and enzyme activity was found to be modulated by palmitoyl-carnitine. In order to link the actions of palmitoyl-carnitine on phospholipid-sensitive protein kinase activity and the already reported role of protein kinase C in cell division, we studied the action of palmitoyl-carnitine on melanoma cell growth by measuring colony forming ability in a soft agar culture system. Palmitoyl-carnitine was found to inhibit cell growth in a dose-dependent manner. These findings suggest that palmitoyl-carnitine (or long-chain acylcarnitine), a naturally occurring metabolite, may play a key role in the onset of cell division. We suggest that the action of palmitoyl-carnitine on phospholipid-dependent protein kinase activity is in part related to the molecular events linking protein kinase C activity and the ionic events in the initiation of cell growth.
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PMID:Modulation by palmitoyl-carnitine of calcium activated, phospholipid-dependent protein kinase activity and inhibition of melanoma cell growth. 316 38

A strong correlation was found between the basal levels of membrane-bound protein kinase C and the ability of B16 melanoma cell sublines (F10, F1, and BL6) to metastasize to the lung after intravenous injection. By treating with tumor-promoting phorbol esters for 1 hr, the low-metastasizing F1 cells exhibited both translocation of protein kinase C from cytosol to plasma membrane and an increase in metastasis to a level comparable to the (untreated) highly metastatic subline F10. Prolonged treatment of melanoma sublines with phorbol 12-myristate 13-acetate for 24 hr resulted in both inactivation of protein kinase C activity and loss of their metastasizing capabilities. Under conditions that induced only the activation of protein kinase C but not its membrane association, no increase in metastasis occurred, suggesting that activation of protein kinase C alone is insufficient to promote metastasis and that its membrane association is also necessary. Exposure of B16 melanoma sublines to phorbol esters for 1 hr had (i) no effect on the growth and morphology of these cells in vivo and in vitro and (ii) a short-term effect (approximately equal to 5 hr) on membrane association of protein kinase C. Nonetheless, in this period, the membrane-bound protein kinase C, probably by influencing cell-surface and cell-attachment properties, increased the retention of circulating melanoma cells in the lung, which eventually led to an increased number of metastatic nodules. The membrane-bound protein kinase C activity also correlated with metastatic ability in rapidly growing cells, growth-arrested cells, and cells growing in a low-Ca2+ medium. The results strongly suggest that the membrane-bound protein kinase C influences hematogenous metastasis of tumor cells and show that tumor promoters like phorbol esters have an additional role in promoting hematogenous spread of cancer in the body.
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PMID:Tumor promoter-induced membrane-bound protein kinase C regulates hematogenous metastasis. 342 45

B16 melanoma cells differentiate upon treatment with retinoic acid (RA). This differentiation process is accompanied by an increase of protein kinase C alpha (PKC alpha) mRNA and protein levels. Overexpression of PKC alpha in these cells results in a more differentiated phenotype, suggesting the importance of this protein in the control of differentiation by RA. The purpose of the study reported here was to determine the subcellular distribution of the RA-induced PKC alpha, whether the RA-induced increase in PKC alpha protein levels was accompanied by an increase in in situ enzyme activity, and whether RA altered AP-1 transcriptional activity. We found that RA treatment increased PKC alpha protein levels in all subcellular compartments examined, but it also induced a selective enrichment in nuclear-associated PKC alpha levels. Treating cells with an active phorbol ester induced translocation of PKC alpha to membrane fractions, but had no effect on nuclear PKC alpha levels. RA also increased PKC enzymatic activity in intact cells as determined by phosphorylation of the PKC-specific endogenous substrate MARCKS. However, while RA induced a five- to eightfold increase in total cellular PKC alpha protein levels, it only increased MARCKS phosphorylation by twofold. In light of the increase in in situ PKC enzyme activity and the enrichment of nuclear PKC alpha, we determined whether AP-1 activity might be increased in RA-treated cells. Use of luciferase reporter gene constructs with or without AP-1 elements transfected into B16 cells indicated that RA induced a four- to fivefold increase in AP-1 transcriptional activity. These results suggest a hypothesis whereby RA-induced nuclear PKC alpha might lead to increased AP-1 activity and show that RA-induced growth inhibition and differentiation are not always accompanied by an inhibition of AP-1 activity as has been proposed by other investigators.
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PMID:Retinoic acid specifically increases nuclear PKC alpha and stimulates AP-1 transcriptional activity in B16 mouse melanoma cells. 749 37

12(S)-Hydroxyeicosatetraenoic acid [12(S)-HETE] is the 12-lipoxygenase metabolite of arachidonic acid. Previously, we have demonstrated that exogenous 12(S)-HETE can activate protein kinase C, increase cell surface expression of integrins, enhance adhesion, induce endothelial cell retraction, and increase experimental metastasis of tumor cells. Because of these prominent effects of exogenous 12(S)-HETE on tumor cell metastatic potential, it is important to determine whether there is endogenous 12(S)-HETE production by tumor cells. In the present study, mRNAs from human, rat, and mouse platelets as well as human colon carcinoma (Clone A), rat Walker carcinoma (W256), and mouse melanoma (B16a) and lung carcinoma (3LL) were reverse transcribed and amplified by polymerase chain reaction with platelet 12-lipoxygenase specific primers. Identity of the polymerase chain reaction fragments was confirmed by sequencing. 12-Lipoxygenase protein was detected by Western blotting. Tumor cell-derived 12-HETE was determined by reverse phase-high performance liquid chromatography analysis. In addition, the effect of endogenous 12(S)-HETE on tumor cells was studied by using a platelet-type 12-lipoxygenase selective inhibitor (N-benzyl-N-hydroxy-5-phenylpentanamide). Our results suggest that some tumor cells express platelet-type 12-lipoxygenase mRNA, protein and metabolize arachidonic acid to 12(S)-HETE and that endogenous 12(S)-HETE, like the exogenous 12(S)-HETE, may play an important role in tumor cell adhesion to matrix in vitro and lung colonization in vivo.
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PMID:Endogenous 12(S)-HETE production by tumor cells and its role in metastasis. 751 Oct 46

Phorbol 12-myristate 13-acetate (PMA) is a tumour promotor that acts as a potent protein kinase C (PKC) activator that has significant effects on tumour cell attachment and spreading. We tested whether these effects of PMA may be observed in human melanoma cells, and whether a specific response to extracellular matrix proteins may be mediated by shifts in the expression of beta 1 integrins. We used cell attachment assays, video time lapse cell spreading assays, flow cytometry, function blocking monoclonal antibodies (MAbs) and PKC inhibitor Calphostin C to address these questions. We established that PMA induces a rapid and temporary enhancement of cell attachment and spreading which was not accompanied by a significant change in the expression of beta 1 integrins. Spreading of melanoma cells that were not stimulated with PMA could be significantly blocked with a function blocking MAb (clone P4C10) against the common beta 1 integrin subunit. The spreading and attachment of the PMA treated cells was also significantly reduced, but less so, after MAb treatment. The PMA enhanced cell attachment and spreading could be effectively blocked by RGD sequences and PKC inhibitor. Taken together, our data indicate that PMA induces a rapid and temporary ECM-dependent enhancement of melanoma cell attachment and spreading, and that the response to ECM components appears not to be due to significant shifts in beta 1 integrin expression, but rather to activation of beta 1 integrins.
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PMID:Phorbol ester induced rapid attachment and spreading of melanoma cells and the role of extracellular matrix proteins. 751 59

The process of tumor cell invasion of the basement membrane is proposed to consist of three steps: attachment, local proteolysis and migration. 12-(S)-HETE, a 12-lipoxygenase metabolite of arachidonic acid, upregulates surface expression of integrin cytoadhesins and an autocrine motility factor receptor, suggesting that this metabolite may play an important regulatory function in tumor cell invasion. In the present study, we determined whether 12-(S)-HETE affects surface expression and/or release of cathepsin B, a cysteine protease that has been implicated in focal degradation of basement membrane. Secretion and distribution of cathepsin B was evaluated in two model systems for various stages of neoplastic progression: (i) murine B16 melanoma lines of low (B16-F1) and high (B16a) lung colonization potential, and (ii) immortalized and ras-transfected MCF-10 human breast epithelial cells that differ in their invasive capacities in vitro. In the B16a cells, 12-(S)-HETE induced release of native and latent cathepsin B activity and concomitantly reduced cell-associated cathepsin B immunoreactivity. In contrast, 12-(S)-HETE did not induce the release of cathepsin B from B16-F1 cells, suggesting that there may be an enhanced response to 12-(S)-HETE in more malignant cells. This was confirmed in the MCF-10 system, in which 12-(S)-HETE was able to induce the release of cathepsin B from the ras-transfected cells, but not from the immortal cells. A simultaneous reduction in staining for cathepsin B was observed in the ras-transfected cells, but not in their immortal counterparts. The release of cathepsin B may be mediated by PKC as pretreatment of B16a cells with the selective PKC inhibitor calphostin C, but not with the PKA inhibitor H8, prevented the stimulated release of cathepsin B. In B16a cells, the release of cathepsin B was accompanied by a translocation toward the cell periphery of vesicles staining for cathepsin B, resulting in focal areas of accumulation of cathepsin B. After 12-(S)-HETE stimulation of the ras-transfected MCF-10 cells, cathepsin B was distributed homogeneously on the apical surface. Thus, 12-(S)-HETE can upregulate the surface expression on tumor cells of proteins able to mediate each of the three steps of tumor cell invasion: adhesion, degradation, and migration.
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PMID:A lipoxygenase metabolite, 12-(S)-HETE, stimulates protein kinase C-mediated release of cathepsin B from malignant cells. 752 40


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