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Inhibition of Melanin Synthesis by Cystamine in Human Melanoma Cells

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Inhibition of Melanin Synthesis by Cystamine in Human Melanoma Cells CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Inhibition of Melanin Synthesis by Cystamine in Human Melanoma Cells Ling Qiu, Mei Zhang, Rick A. Sturm,* Brooke Gardiner,* Ian Tonks, Graham Kay, and Peter G. Parsons Queensland Cancer Fund Laboratories, Queensland Institute of Medical Research and University of Queensland Joint Experimental Oncology Program, Herston, Queensland, Australia; *Center for Molecular and Cell Biology, University of Queensland, Australia In studies to determine whether pigmentation can be of MM96L and HeLa cells. Cystamine treatment regulated physiologically by thiols, human melanoma lowered the degree of cross-linking of the pigment- cells (MM418c5)and melanocytes were found to ation antigen gp75/TRP-1 in MM418c5 cells. become depigmented when cultured continuously in Tyrosinase protein and mRNA levels in MM418c5 50 mM cystamine. Cystamine was depleted from the cells were not affected by cystamine. The results culture medium and the treatment was nontoxic and show that cystamine at a concentration close to reversible. Cysteamine, dithiothreitol, and phenyl- physiologic levels has multiple effects on the melano- thiourea were less effective, and glutathione, genic pathway. In amelanotic cells, tyrosinase has a cysteine, and cystine were inactive. Tyrosinase (dopa short half-life and is readily inhibited by cystamine/ oxidase)activity was not greatly affected except for cysteamine whereas tyrosinase in the more mature induction of a lag period. In contrast, tyrosinase melanosomes of the pigmented cell appears to be activity in an amelanotic melanoma cell line less accessible to proteolytic and thiol attack. (MM96L)was rapidly inhibited without consumption Inhibition of melanin synthesis in the latter cell type of cystamine/cysteamine, in association with the may arise to a signi®cant degree from reduction of generation of free thiol in the culture medium, and cystamine to cysteamine, which sequesters quinones. could be enhanced by the cystine transport inhibitor, Key words: cystamine/depigmentation/human melanoma glutamate. Tyrosinase expressed by a recombinant cells/melanin/tyrosinase. J Invest Dermatol 114:21±27, vaccinia virus was inhibited by cystamine treatment 2000 number of pigmentation genes expressed in (Benedetto et al, 1982) and in the tabby syndrome in mice melanocytes and their promoter sequences have (Robertson and Blecher, 1987). The depigmenting activity been cloned (del Marmol and Beermann, 1996) but reported for high-dose, local application of the naturally occurring there is still incomplete understanding of how disul®de cystamine (Chavin and Schlesinger, 1966; Bolognia et al, A melanin synthesis is regulated in vitro or in vivo.A 1995) and for cysteaminylphenols (Pankovich et al, 1990) appears to knowledge of such mechanisms may allow pigment synthesis to be arise from the destruction of melanocytes, due to a reaction with manipulated, for the purposes of photoprotection or for driving molecules which are not necessarily speci®c to pigment synthesis melanoma cells into a state of permanent differentiation. Tyrosinase (Parsons et al, 1991). Little consideration has been given to the is a major enzyme in this pathway, converting tyrosine to dopa possibility that cystamine and its reduced monomer cysteamine may products for polymerization to melanin (Benedetto et al, 1982; regulate melanization in viable cells at the physiologic level. Hearing and Tsukamoto, 1991). Being a copper enzyme, tyrosinase Inside the cell, cystamine/cysteamine may interact with many is susceptible to inhibition by naturally occurring thiols including proteins via disul®de exchange reactions, leading for example to the glutathione (GSH), cysteine, and proteins with reactive thiols such mobilization of zinc ions from metallothionein (Maret, 1995). as thioredoxin (Wood and Schallreuter, 1991; Jimbow et al, 1992; Inhibition of GSH synthesis (Bolognia et al, 1995), transglutaminase Ando et al, 1993; Naish-By®eld and Riley, 1998). Alternatively, (Birckbichler et al, 1981), monoamine oxidase and glucose-6- thiols may react with quinone intermediates (Ito and Prota, 1977) phosphate dehydrogenase (Terada, 1994), and activation of to divert pigment synthesis from eumelanin (black) to pheomelanin lysosomal proteases (Pisoni et al, 1990; Jeitner et al, 1998) by (red/yellow). Elevated levels of thiols including GSH have been cystamine have been reported. Cystamine has been used to relieve linked to pheomelanin formation or lack of pigment in humans cystine accumulation in cystic ®brosis patients (Butler and Zatz, 1984). In cultured cells cystamine promotes the uptake of cystine Manuscript received December 7, 1998; revised September 14, 1999; via a glutamate-sensitive transporter with consequent increased accepted for publication October 7, 1999. synthesis of glutathione (Issels et al, 1988). Cysteamine inhibits Reprint requests to: Dr. P.G. Parsons, Queensland Cancer Fund human immunode®ciency virus replication (Bergamini et al, 1994) Laboratories, Queensland Institute of Medical Research and University of and activates neuro®bromatosis kB in lymphocytes (Goldstone et al, Queensland Joint Experimental Oncology Program, Herston, Queensland, Australia 4029. Email: [email protected] 1995). The effects of cysteamine may vary considerably in different Abbreviations: BCIP, 4-bromo-5-chloroindolyl-3-phosphate; DTNB, cell types, inducing hsp 27, hsp 90, and heme oxygenase-1, forming 5,5-dithiobis(2-nitrobenzoic acid); GSH, glutathione; NBT, nitroblue peroxidase-positive granules and damaging mitochondria in astro- tetrazolium; TRP-1, tyrosinase-related protein-1. cytes but not in glial cells (Chopra et al, 1995). 0022-202X/00/$15.00 ´ Copyright # 2000 by The Society for Investigative Dermatology, Inc. 21 22 QIU ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Synthetic b-aminoethyl disul®des structurally related to hist- amine H2 agonists are reduced to thiols by cultured melanoma cells (Fechner et al, 1994), with inhibition of tyrosinase activity and loss of pigment synthesis. Study of the simplest member of this family, cystamine, at nontoxic levels has now shown that it slightly reduces tyrosinase activity in pigmented melanoma cells and inhibits pigment synthesis. MATERIALS AND METHODS Cell culture MM96E, MM96L, MM418c5, and HeLa cells (Fechner et al, 1994) were grown in RPMI 1640 culture medium supplemented with 5% heat-inactivated fetalbovine serum. Human melanocyteswere grown in culture media supplemented with 10% fetal bovine serum, 10 ng per ml 12-O-tetradecanoyl-phorbol-13-acetate and 6 ng per ml cholera toxin. All cell lines were adherent monolayers grown at 37°C in a humidi®ed atmosphere containing 5% CO2/air. Cell lines were tested routinely for Mycoplasma using a Hoescht 33245 staining technique (Chen, 1977). Cell survivals were determined by incorporation of 3H-thymidine as previously described (Fechner et al, 1994), 5±7 d after commencement of drug Figure 1. Survival of cells treated for 7 d with cystamine or cysteine. treatment. (A) Cystamine; (B) cysteine. d, MM418c5; h, MM96L; s, HeLa. Points Tyrosinase (dopa oxidase) activity was determined in cell lysates as are mean 6 SD (n = 3) described (Fechner et al, 1994), except that the substrate solution contained 1 mM dopa, 3 mM 3-methyl-2-benzothiazolinone hydrazone and 0.1% Triton X-100 in 50 mM phosphate buffer, pH 6.8. Melanin was ampicillin resistance gene (as an end-®lled BspHI fragment). The pSV-b- determined by solubilization of cell pellets in Soluene 350 (Fechner et al, galactosidase vector containing the SV40 promoter and enhancer was 1994). Free thiols were detected by adding 50 mlof 3 mM dithiobisnitro- obtained from Promega. benzoic acid (DTNB) to 50 mlof culturemedium, or supernatant obtained by lysis of 2 3 106 cells in 1% Triton X-100 in 50 mM phosphate buffer Expression of tyrosinase encoded by vaccinia virus The vaccinia (0.5 ml) followed by centrifugation (9000 3 g for 10 min). After 30 min the virus construct, where the human tyrosinase gene is activated by the absorbance at 415 nm was read on an enzyme-linked immunosorbent assay vaccinia p7.5 early late promoter (Yee et al, 1996), was kindly provided by reader. Dr. C. Yee. It was grown in CV-1 cells by Dr. Rajiv Khanna and a pool used at 1/100 dilution on cell lines cultured in 96 well plates (105 cells per Western and northern blotting Whole cell lysates were subjected to well). After infection for 24 h, the monolayer was washed once with western blotting using the 2B7 mouse monoclonal antibody to tyrosinase phosphate-buffered saline (0.1 M NaC1, 50 mM phosphate, pH 7.3) and (McEwan et al, 1988) and B8G3 antibody against TRP-1 and incubated with 100 mlof 0.1% Triton X-100, 3 mM 3-methyl-2- immunostaining with alkaline phosphatase secondary antibody and benzothiazolinone hydrazone and 1 mM dopa in 50 mM phosphate, BCIP/NBT substrates as described (Wong et al, 1994), except that lysates pH 6.8. When a red color developed (20±60 min), 100 mlof ethanolwas were not treated with dithiothreitol(DTT). Equalloadingwas achieved by added to inactivate the virus and the mixture was carefully aspirated on to determination of lysate protein and con®rmed in some experiments by another 96 well plate for absorbance measurement at 490 nm on an Coomassie Blue staining of a gel run in parallel or by reprobing the enzyme-linked immunosorbent assay reader. The virus titer was membrane with monoclonal antibody IFA against intermediate ®laments, determined
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