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)

We previously showed that growth of the nontumorigenic, immortal murine melanocyte line Mel-ab correlates with the depletion of protein kinase C (PKC), whereas quiescence is associated with elevated levels of this enzyme (Brooks G, et al., Cancer Res 51: 3281-3288, 1991). Here we report responses that occur in these cells downstream of PKC activation or downregulation. We examined induction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS) gene expression in Mel-ab melanocytes and in their transformed counterparts, B16 melanoma cells. Exposure of quiescent Mel-ab cells to the PKC-activating phorbol esters TPA or sapintoxin A at 81 nM for 2 h increased levels of mRNA for six of seven TIS genes examined (twofold to 80-fold increase in steady-state RNA levels for TIS 1, 7, 8, 11, 21, and 28 (c-fos); TIS 10 expression was not affected). No induction of TIS gene expression was observed either in growing Mel-ab cells maintained in 324 nM phorbol 12,13-dibutyrate or in B16 cells previously unexposed to phorbol esters, in which normal PKC levels were endogenously depressed. The cAMP-elevating agents choleratoxin (10 nM) and dibutyryl cyclic AMP (2.5 mM) increased levels of TIS mRNA (with the exception of TIS 10) in both proliferating Mel-ab and B16 cells, suggesting that downregulation of the PKC pathway is specific and not a consequence of a general inhibition of all signalling pathways.
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PMID:Differential induction of 12-O-tetradecanoylphorbol-13-acetate sequence gene expression in murine melanocytes and melanoma cells. 137 17

The growth of Demel human metastatic melanoma cells was inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA) and other nonphorbol tumor promoters including palytoxin and okadaic acid. Using flow cytometry, we have demonstrated that the cells arrested growth in G1 and G2 phases of the cell cycle. Detailed analysis of the kinetics of the growth arrest in unsynchronized cells showed that (a) the growth arrest was transient and peaked 16-20 h following addition of TPA; (b) effects of TPA on cell growth began within 1-2 h after the addition; and (c) cells completed S phase and arrested in G2. In addition, TPA induced a pronounced morphological change, which peaked by 1 h and gradually subsided over 24 h. In populations of cells synchronized in G1 using lovastatin, (a) addition of TPA blocked the onset of DNA synthesis up to the end of G1; (b) the lag between addition of the drug and onset of DNA synthesis was less than 30 min; and (c) addition of TPA at the end of G1 prevented the increased phosphorylation of p34cdc2, as determined by immunoprecipitation. The experiments reported here show that TPA transiently blocked the proliferation of Demel melanoma cells at the G1-S border and in G2, thus preventing cells from progressing through the cell cycle. These experiments suggest that pathways involving protein kinase C interact with and rapidly alter the molecular pathways involving p34cdc2 which regulate the onset of DNA synthesis and the G2-M transition.
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PMID:12-O-tetradecanoylphorbol-13-acetate induces transient cell cycle arrest in G1 and G2 in metastatic melanoma cells: inhibition of phosphorylation of p34cdc2. 139 Mar 35

We examined the expression of interleukin-6 (IL-6) by 12 established human melanoma cell lines. Two constitutively produced low levels of IL-6 protein, as measured by enzyme-linked immunosorbent assay. Cells from these two lines, as well as those from two non-IL-6-producing cell lines, contained IL-6-specific mRNA as demonstrated by Northern hybridization. Treatment of the two IL-6-producing melanoma cell lines with interleukin-1 beta, tumor necrosis factor-alpha, or phorbol myristate acetate caused a marked increase in IL-6 production. These induction signals failed to stimulate IL-6 production in the nonproducing cells, even those that expressed IL-6 mRNA. IL-6 did not appear to act as an autocrine growth factor since the addition of exogenous human recombinant IL-6 or polyclonal anti-IL-6 antibody did not alter cellular proliferation. The production of this multifunctional cytokine by tumors may play a role in tumor-host interactions and this should be recognized in the design of biologic therapy trials.
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PMID:Interleukin-6 production by human melanoma cell lines. 139 Dec 35

To investigate the mechanism(s) by which all-transretinoic acid (RA) inhibits cell growth, we studied its effect on the expression of c-fos and c-jun in B16 melanoma cells. RA differentially inhibited proto-oncogene induction by mitogens, such as phorbol 12-myristate 13-acetate and serum. Suppression of c-fos was achieved with doses of RA as low as 10(-10) M and required pretreatment of cells with RA for a minimum of 2 h. In contrast, inhibition of c-jun required pretreatment for greater than 16 h with at least 10(-8) M RA and coincided with the observed decrease in cell growth. RA blocked c-fos induction by inhibiting transcription. This inhibition of transcription occurs through the serum response element (SRE), since the SRE alone was sufficient to confer down-regulation by RA to a minimal c-fos promoter construct. Thus, the SRE plays a critical role in the suppression of c-fos transcription by RA.
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PMID:Inhibition of mitogen-induced c-fos expression in melanoma cells by retinoic acid involves the serum response element. 140 Mar 13

Based on the clinicopathological classification of distinct stages of tumor progression in the melanocytic system, we have investigated the in vitro growth patterns and requirements of normal melanocytes and melanocytes isolated from different lesions of melanoma progression. Normal melanocytes depend on a combination of insulin-like growth factor (IGF-I) or insulin, 12-O-tetradecanoyl phorbol-13-acetate (TPA), alpha-melanocyte stimulating hormone (alpha-MSH), and basic fibroblast growth factor (bFGF) for in vitro proliferation. Nevus cells display a reduced need for TPA and are largely independent of bFGF. Both melanocytes and nevus cells have a finite lifespan in vitro and show no spontaneous transformation, whereas melanoma cells can be grown indefinitely in vitro. Cells from primary melanomas require only IGF-I or insulin for continuous growth, and metastatic melanoma cells can proliferate in base medium without addition of any growth factors or proteins. This progressive growth autonomy is paralleled by an increased competence for endogenous growth factor production. Among these growth factors, bFGF and melanoma growth-stimulatory activity (MGSA) act in an autocrine fashion. Melanoma-derived growth factors without apparent autocrine function, such as platelet-derived growth factor A and B (PDGF-A and PDGF-B) and transforming growth factor-alpha (TGF-alpha), might still be important for melanoma growth by stimulating surrounding normal fibroblasts, endothelial cells, or keratinocytes to secrete growth-promoting factors. The significance of growth factors such as transforming growth factor-beta (TGF-beta) and melanoma-inhibiting activity II (MIA II), which have a potentially negative autocrine function, remains unknown. The successful propagation of melanocytic cells of all stages of melanoma progression has yielded valuable insight into the mechanisms of growth regulation and malignant transformation.
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PMID:In vitro growth patterns of normal human melanocytes and melanocytes from different stages of melanoma progression. 144 12

The qualitative and quantitative expression of three calmodulin genes (CAM I, CAM II and CAM III) was characterized in human neonatal melanocytes and metastatic melanoma cell lines in the absence and presence of serum, other growth modulators, and/or 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Results indicated that the qualitative expression in melanocytes was the same as that of melanomas, that is, CAM I gene expressed two transcripts, 4.4 kb and 2.1 kb, whereas CAM II and CAM III expressed one transcript each, 1.95 kb and 2.37 kb, respectively. Differential quantitative expression was seen particularly with CAM I. The average levels of both CAM I transcripts in melanomas were less than one-half those of melanocytes. Serum and other growth modulators (including Ca++, isobutyl methyl xanthine, bovine pituitary extract, and insulin) enhanced CAM I and CAM II gene expression in melanocytes; in contrast, the net effect of serum in melanomas was to decrease expression of CAM I and CAM III. This effect was most prominent in melanoma C81-46C. TPA markedly inhibited expression of all three CaM genes in melanocytes; however, in melanomas the net effect of TPA was to increase their expression. CAM I in melanoma C81-46C was the most sensitive to TPA stimulation.
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PMID:Comparison of calmodulin gene expression in human neonatal melanocytes and metastatic melanoma cell lines. 146 90

The purpose of this study was to determine the carcinogenic effect in male rats of a single i.v. injection of N-methyl-N-nitrosourea (MNU) after sequential treatment with cyproterone acetate (for 21 days) and testosterone propionate (for 3 days). This treatment has previously been shown to induce carcinomas of the prostate and other male accessory sex glands. A wide spectrum of non-melanoma skin tumors was found in 38-48% of Wistar (Cpb:WU) rats given this sequential treatment, but only in 5% of rats that received only MNU. Castration long and, particularly, early after MNU markedly reduced this skin tumor response to a 10-13% incidence. The skin tumorigenic efficacy of MNU was dependent on the time between the start of the testosterone propionate treatment and carcinogen administration: MNU injection after 48-50 or 60-63 h induced skin tumors in 17-21% of Wistar rats, whereas injection after 72-74 h induced a 48% incidence. The Fischer F344 and Sprague-Dawley strains were not very sensitive to induction of skin tumors by this approach. Thyroid follicular cell tumors were also induced by MNU only after the hormonal pretreatment, and their induction was influenced by the time of MNU injection as well. The time of MNU injection and rat strain used did not significantly influence the induction of sebaceous-squamous neoplasms of the ear-duct/Zymbal's glands or other tumors. These data indicate that endogenous androgens are critically involved in the later stages of rat skin tumorigenesis and suggest that androgen-induced cell proliferation influences the initiation stage of this process and, possibly, of thyroid tumorigenesis.
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PMID:Induction of skin and thyroid tumors in male rats by N-methyl-N-nitrosourea after sequential treatment with cyproterone acetate and testosterone propionate: effects of castration, rat strain and time of carcinogen injection. 153 74

Novel derivatives of K-252a, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl- 8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibe nzo[a,g]-cycloocta[cde]trinden-1-one, an inhibitor of protein kinases and calmodulin-dependent phosphodiesterase, were synthesized and evaluated for their antitumor activity in vitro and in vivo. Of ten derivatives tested, four were active against the P388 murine leukemia i.p.-i.p. system, although K-252a was inactive. Among these derivatives, KT6124 was selected for further biological evaluation studies because its efficacy was the highest. KT6124 was also active against sarcoma 180 and B16 melanoma. It exerted a relatively broad spectrum of antiproliferative activity against 20 human tumor cell lines in vitro. To determine the mechanism(s) of action underlying the antitumor activity of KT6124, we tested the drug for inhibition of protein kinases, including Ca(2+)- and phospholipid-dependent protein kinase (PKC), in intact A431 human epidermoid carcinoma cells in comparison with the PKC-inhibitory activity of K-252a. KT6124 did not antagonize the action of phorbol 12-myristate 13-acetate (PMA) in A431 cells, whereas K-252a did, suggesting that KT6124 may not act on protein kinases in the cells. The interaction of KT6124 with DNA in living cells was examined by the alkaline elution method. KT6124 apparently exhibited DNA scission both dose- and time-dependently in the target cells. The DNA breakage was dependent on proteinase K treatment, suggesting its possible interaction with DNA-related enzyme(s). These results indicate that KT6124 exerts antitumor activity by acting on DNA or on DNA-related enzyme(s) in tumor cells rather than via the inhibition of protein kinases.
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PMID:Antitumor effect of KT6124, a novel derivative of protein kinase inhibitor K-252a, and its mechanism of action. 153 71

Murine and human melanoma cells differ relatively reliably from non-tumorigenic melanocytes in certain biological properties. When cultured at low pH, melanocytes tend to be pigmented and melanoma cells unpigmented. The growth of virtually all metastatic melanoma cells is inhibited by phorbol esters such as TPA (12-O-tetradecanoyl phorbol-13-acetate), which stimulate melanocyte growth. Melanocytes fail to grow in suspension culture or produce tumours when implanted in animals, while many melanoma lines can do both. Here we studied which of these properties were dominant in hybrid cells formed by fusion of drug-resistant murine B16-F10RR melanoma cells to melanocytes of the albino and brown lines, melan-c and melan-b. The albino melanocytes are unpigmented but well-differentiated, the brown melanocytes produce pale brown pigment and the melanoma cells are unpigmented under the conditions used. All hybrid colonies observed produced black pigment, except some melan-b/melanoma hybrids when growing sparsely with TPA. Thus pigmentation was generally dominant. 14/15 hybrid lines showed stimulation of proliferation by TPA, as do melanocytes. Most hybrid lines showed no or reduced capacity for growth in suspension, though some grew better in suspension when TPA was present. There was marked suppression of the tumorigenicity of the parental melanoma cells in 4/8 hybrids examined, and tumorigenicity was reduced in the others, despite considerable chromosome loss by the passage level tested. Thus most properties of the non-tumorigenic pigment cells were dominant, as often observed for other cell lineages, and providing further evidence for gene loss in the genesis of malignant melanoma.
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PMID:Suppression of properties associated with malignancy in murine melanoma-melanocyte hybrid cells. 156 63

Mouse monoclonal antibodies (MoAbs), IKH-1 and IKH-2, were produced against cloned human melanoma cells, KHm-6, which were cultured with 12-O-tetradecanoylphorbol-13-acetate (TPA) and processed by formalin fixation and alcohol dehydration (FFAD). According to the biochemical analysis, antigenic substances which reacted with IKH-1 were 34.0-60.0 kDa glycoproteins, and those which reacted with IKH-2 were 33.5, 34.5 and 36.0 kDa glycoproteins. Immunoelectron microscopy revealed that reaction products of IKH-1 were seen in some membranous vesicles, premelanosomes and cell membrane of TPA-treated KHm-6 cells, while IKH-2 recognized only premelanosomal structures. Immunohistochemical tests revealed that IKH-1 and IKH-2 have a high sensitivity (94.0% and 85.0%, respectively) to formalin-fixed, paraffin-embedded (FFPE) tissue sections of malignant melanomas. IKH-1 had a high specificity and IKH-2 and 100% specificity to FFPE tissue sections of melanocytic lesions.
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PMID:Monoclonal anti-melanoma antibodies IKH-1 and IKH-2 which work on formalin-fixed, paraffin embedded tissues: characterization, clinical trials and comparative studies with HMB-45. 159 Dec 23


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