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Role of $K^+$-$Cl^-$-cotransporter in the Apigenin-induced Stimulation of Melanogenesis in B16 Melanoma Cells  

Lee, Yong-Soo (College of Pharmacy, Duksung Women's University)
Publication Information
YAKHAK HOEJI / v.52, no.6, 2008 , pp. 500-506 More about this Journal
Abstract
Apigenin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. In this study we found that apigenin stimulated melanin synthesis in a dose-dependent manner in B16 murine melanoma cells. Since in our previous study $K^+$-$Cl^-$-cotransport (KCC) has been shown to mediate the mechanism of action of apigenin in neuronal cells, we further investigated the role of KCC in the melanogenesis-stimulating effect of apigenin in B16 cells. At nontoxic concentrations apigenin induced $Cl^-$-dependent $K^+$ efflux, a hallmark of KCC activity, which was markedly prevented by a specific KCC inhibitor R-(+)-[(2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetic acid (DIOA). These results indicate that KCC is functionally present, and activated by apigenin in the B16 cells. In addition, the apigenin-induced stimulation of melanogenesis was also significantly inhibited by DIOA. NEthylmaleimide (NEM), a known KCC activator, induced $Cl^-$ efflux and stimulated melanogenesis in a concentration-dependent fashion. Both effects of NEM were significantly inhibited by DIOA. Taken together, these results suggest that apigenin can modulate melanogenesis through the activation of a membrane ion transporter, KCC in B16 cells. These results further suggest that apigenin may be a good candidate in the therapeutic strategy for hypopigmentation disorders, such as vitiligo.
Keywords
$K^+$-$Cl^-$-cotransport; apigenin; B16 melanoma cell; melanogenesis; vitiligo;
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Times Cited By KSCI : 7  (Citation Analysis)
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1 Choi, S. I., Jeong, C. S., Cho, S. Y. and Lee, Y. S. : Mechanism of apoptosis induced by apigenin in HepG2 human hepatoma cells: involvement of reactive oxygen species generated by NADPH oxidase. Arch. Pharm. Res. 30, 1328 (2007)   과학기술학회마을   DOI   ScienceOn
2 Shindo, K., Saito, E., Sekiya, M., Matsui, T. and Koike, Y. : Antioxidative activity of the flower of Torenia fournieri. Nat. Med. (Tokyo) 62, 247 (2008)
3 Shukla, S. and Gupta, S. : Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation. Free Radic. Biol. Med. 44, 1833 (2008)   DOI   ScienceOn
4 Lee, K. E., Sim, G. S., Kim, J. H., Park, S. M., Lee. B. C., Yun, Y. P., Zhang, Y. H. and Pyo, H. B. : Effects of the Scirpi rhizoma on antixodiation and melanogenesis. Yakhak Hoeji 48, 323 (2004)
5 Lauf, P. K., Bauer, J., Adragna, N. C., Fujise, H., Zade-Oppen, A. M., Ryu, K. H. and Delpire, E. : Erythrocyte K-Cl cotransport: properties and regulation. Am. J. Physiol. 263, C917 (1992)   DOI
6 Greger, R. and Schlatter, E. : Properties of the basolateral membrane of the cortical thick ascending limb of Henle's loop of rabbit kidney. A model for secondary active chloride transport. Pflugers Arch. 396, 325 (1983)   DOI   ScienceOn
7 Wisman, K. N., Perkins, A. A., Jeffers, M. D. and Hagerman, A. E. : Accurate assessment of the bioactivities of redox-active polyphenolics in cell culture. J. Agric. Food Chem. 56, 7831 (2008)   DOI   ScienceOn
8 Nitoda, T., Isobe, T. and Kubo, I. : Effects of phenolic compounds isolated from Rabdosia japonica on B16-F10 melanoma cells. Phytother. Res. 22, 867 (2008)   DOI   ScienceOn
9 Ohguchi, K., Akao, Y. and Nozawa, Y. : Stimulation of melanogenesis by the citrus flavonoid naringenin in mouse B16 melanoma cells. Biosci. Biotechnol. Biochem. 70, 1499 (2006)   DOI   ScienceOn
10 Takeyama, R., Takekoshi, S., Nagata, H., Osamura, R. Y. and Kawana, S. : Quercetin-induced melanogenesis in a reconstituted three-dimensional human epidermal model. J. Mol. Histol. 35, 157 (2004)   DOI   ScienceOn
11 Bentley, N. J., Eisen, T. and Goding, C. R. : Melanocytespecific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator. Mol. Cell. Biol. 14, 7996 (1994)   DOI   PUBMED
12 Molina, D. M., Grewal, S. and Bardwell, L. : Characterization of an ERK-binding domain in microphthalmia-associated transcription factor and differential inhibition of ERK2-mediated substrate phosphorylation. J. Biol. Chem. 280, 42051 (2005)   DOI   ScienceOn
13 Ma, X., Li, Y. F., Gao, Q., Ye, Z. G., Lu, X. J., Wang, H. P., Jiang, H. D., Bruce, I. C. and Xia, Q. : Inhibition of superoxide anion-mediated impairment of endothelium by treatment with luteolin and apigenin in rat mesenteric artery. Life Sci. 83, 110 (2008)   DOI   ScienceOn
14 Lee, J. H., Zhou, H. Y., Cho, S. Y., Kim, Y. S., Lee, Y. S. and Jeong, C. S. : Anti-inflammatory mechanisms of apigenin: inhibition of cyclooxygenase-2 expression, adhesion of monocytes to human umbilical vein endothelial cells, and expression of cellular adhesion molecules. Arch. Pharm. Res. 30, 1318 (2007)   과학기술학회마을   DOI   ScienceOn
15 Caltagirone, S., Rossi, C., Poggi, A., Ranelletti, F. O., Natali, P. G., Brunetti, M., Aiello, F. B. and Piantelli, M. : Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int. J. Cancer 87, 595 (2000)   DOI   ScienceOn
16 Wang, W., Heideman, L., Chung, C. S., Pelling, J. C., Koehler, K. J. and Birt, D. F. : Cell-cycle arrest at $G_2$/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol. Carcinog. 28, 102 (2000)   DOI   ScienceOn
17 Adragna, N. C., White, R. E., Orlov, S. N. and Lauf, P. K. : KCl cotransport in vascular smooth muscle and erythrocytes: possible implication in vasodilation. Am. J. Physiol. 278, C381 (2000)   DOI
18 Lauf, P. K., Bauer, J., Adragna, N. C., Fujise, H., Zade-Oppen, A. M., Ryu, K. H. and Delpire, E. : Erythrocyte K-Cl cotransport: properties and regulation. Am. J. Physiol. 263, C917 (1992)   DOI
19 Rezai-Zadeh, K., Ehrhart, J., Bai, Y., Sanberg, P. R., Bickford, P., Tan, J. and Shytle, R. D. : Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J. Neuroinflammation 5, 41 (2008)   DOI   ScienceOn
20 Kim, Y. J., Kang, K. S. and Yokozawa, T. : The anti-melanogenic effect of pycnogenol by its anti-oxidative actions. Food Chem. Toxicol. 46, 2466 (2008)   DOI   ScienceOn
21 Kim, J. A., Kang, Y. S. and Lee, Y. S. : Involvement of $K%+-Cl^-$-cotransport in the apoptosis induced by N-ethylmaleimide in HepG2 human hepatoblastoma cells. Eur. J. Pharmacol. 418, 1 (2001)   DOI   PUBMED   ScienceOn
22 Nagata, H., Takekoshi, S., Takeyama, R., Homma, T. and Yoshiyuki Osamura, R. : Quercetin enhances melanogenesis by increasing the activity and synthesis of tyrosinase in human melanoma cells and in normal human melanocytes. Pigment Cell Res. 17, 66 (2004)   DOI   ScienceOn
23 Seiberg, M. : Kerationcytemelanocyte interaction during melanosome transfer. Piment Cell Res. 14, 236 (2001)   DOI   ScienceOn
24 Hearing, V. J. and Tsukamoto, K. : Biochemical control of melanogenesis and melanosomal organization. J. Invest. Dermatol. Symp. Proc. 4, 24 (1999)
25 Cho, Y. H., Lee, B. C., Kim, J. H., Kim, J. H., Pyo, H. B., Zhang, Y. H. and Park, H. D. : Effect of Aetemisia anomala S. Moore on antioxidant activity and melanogenesis, Kor. J. Pharmacognosy 36, 273 (2005)   과학기술학회마을
26 Weil-Maslansky, E., Gutman, Y. and Sasson, S. : Insulin activates furosemide-sensitive $K^+\;and\;Cl^-$ uptake system in BC3H1 cells. Am. J. Physiol. 267, C932 (1994)   DOI
27 Fujii, T., Ohira, Y., Itomi, Y., Takahashi, Y., Asano, S., Morii, M., Takeguchi, N. and Sakai, H. : Inhibition of P-type ATPases by [(dihydroindenyl)oxy]acetic acid (DIOA), a $K^+-Cl^-$-cotransporter inhibitor. Eur. J. Pharmacol. 560, 123 (2007)   DOI   PUBMED   ScienceOn
28 Cabanes, J., Chazarra, S. and GarciaCarmona, F. : Kojic acid, a cosmetic skin whitening agent, is a slowbinding inhibitor of catecholase activity of tyrosinase. J. Pharm. Pharmacol. 46, 982 (1994)   DOI   PUBMED   ScienceOn
29 Ellison, D. H., Velazquez, H. and Wright, F. S. : Stimulation of distal potassium secretion by low lumen chloride in the presence of barium. Am. J. Physiol. 248, F638 (1985)
30 Cossins, A. R. and Gibson, J. S. : Volume-sensitive transport systems and volume homeostasis in vertebrate red blood cells. J. Exp. Biol. 200, 343 (1997)   PUBMED
31 Kim, M. H., Jeong, C. S., Yoon, H. R., Kim, G. H. and Lee, Y. S. : Involvement of $K^+-Cl^-$-cotransport in the apigenin-Induced generation of reactive oxygen species in IMR-32 human neuroblastoma cells. J. Appl. Pharmacol. 14, 137 (2006)   과학기술학회마을
32 Yan, G. X., Chen, J., Yamada, K. A., Kleber, A. G. and Corr, P. B. : Contribution of shrinkage of extracellular space to extracellular $K^+$ accumulation in myocardial ischaemia of the rabbit. J. Physiol. (London) 490, 215 (1996)   DOI
33 Peterson, J. and Dwyer, J. : Flavonoids: dietary occurrence and biochemical activity. Nutr. Res. 18, 1995 (1988)   DOI   ScienceOn
34 Plochmann, K., Korte, G., Koutsilieri, E., Richling, E., Riederer, P., Rethwilm, A., Schreier, P. and Scheller, C. : Structure-activity relationships of flavonoid-induced cytotoxicity on human leukemia cells. Arch. Biochem. Biophys. 460, 1 (2007)   DOI   ScienceOn
35 Perry, P. B. and O'Neill, W. C. : Swelling-activated K fluxes in vascular endothelial cells: volume regulation via K-Cl cotransport and K channels. Am. J. Physiol. 265, C763 (1993)   DOI
36 Psotova, J., Chlopcikova, S., Miketova, P., Hrbac, J. and Simanek, V. : Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempherol, luteolin and quercetin. Phytother. Res. 18, 516 (2004)   DOI   ScienceOn
37 Finn, G. J., Creaven, B. S. and Egan, D. A. : Activation of mitogen activated protein kinase pathways and melanogenesis by novel nitro-derivatives of 7-hydroxycomarin in human malignant melanoma cells. Eur. J. Pharm. Sci. 26, 16 (2005)   DOI   ScienceOn
38 Amlal, H., Paillard, M. and Bichara, M. : $Cl^-$-dependent $NH_4^{+_4}$ transport mechanisms in medullary thick ascending limb cells. Am. J. Physiol. 267, C1607 (1994)   DOI
39 Rivera, C., Voipio, J., Payne, J. A., Ruusuvuori, E., Latineen, H., Lamsa, K., Pirvola, U., Saarma, M. and Kaila, K. : The $K^+/Cl^-$ co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251 (1999)   DOI   PUBMED   ScienceOn
40 Sim, G. S., Lee, B. C., Cho, H. S., Lee, J. W., Kim, J. H., Lee, D. H., Kim, J. H., Pyo, H. B., Moon, D. C., Oh, K. W., Yun, Y. P. and Hong, J. T. : Structure activity relationship of antioxidative property of flavonoids and inhibitory effect on matrix metalloproteinase activity in UVA-irradiated human dermal fibroblast. Arch. Pharm. Res. 30, 290 (2007)   과학기술학회마을   DOI   ScienceOn
41 Hill, H. Z., Li, W., Xin, P. and Mitchell, D. L. : Melanin: a two edged sword? Pigment Cell Res. 10, 158 (1997)   DOI   ScienceOn
42 Choi, M. Y., Song, H. S., Hur, H. S. and Sim, S. S. : Whitening activity of luteolin related to the inhibition of cAMP pathway in alpha-MSH-stimulated B16 melanoma cells. Arch. Pharm. Res. 31, 1166 (2008)   과학기술학회마을   DOI   ScienceOn
43 Panda, S. and Kar, A. : Apigenin (4',5,7-trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxan-induced diabetic mice. J. Pharm. Pharmacol. 59, 1543 (2007)   DOI   ScienceOn
44 Marmol, V. and Beermann, F. : Tyrosinase and related protein in mammalian pigmentation. FEBS Letters 381, 165 (1996)   DOI   ScienceOn