Stimulation of Cloudman melanoma tyrosinase activity occurs predominantly in G2 phase of the cell cycle.
A widely accepted notion is that an increasing cellular cyclic AMP (cAMP) concentration is prerequisite for increasing tyrosinase activity and melanin synthesis and for regulating proliferation of pigment cells. alpha-Melanocyte stimulating hormone (alpha-MSH) increases cAMP and tyrosinase activity in Cloudman melanoma cells. Prostaglandins (PGs) E1 and E2 increase melanoma cell tyrosinase activity and inhibit proliferation. Both PGs, but not alpha-MSH, block the progression of Cloudman melanoma cells from G2 phase of the cell cycle into M or G1. Only PGE1 and not PGE2 causes an elevation of cellular cAMP concentrations. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine (DDA) at 5 x 10(-4) M effectively blocks the increased cAMP synthesis by cells treated with 10 micrograms/ml PGE1. The addition of DDA, however, enhances the melanogenic response of melanoma cells to 10 micrograms/ml PGE1 or PGE2, 10(-7) M alpha-MSH, 10(-4) M isobutylmethylxanthine, 10(-4) M dibutyryl cyclic AMP. DDA also augments the effects of PGE1 or PGE2 on the melanoma cell cycle. Moreover, when DDA is added concomitantly with alpha-MSH, more cells are recruited into G2 than observed in untreated controls. Neither alpha-MSH nor DDA alone has any effect on the cell cycle. These findings undermine the role of cAMP in the melanogenic process and suggest that blocking melanoma cells in G2 may be required for the remarkable stimulation of tyrosinase activity observed with PGE1 or PGE2 alone or in combination with DDA. The observed block in G2 may be essential for the synthesis of sufficient mRNA, which is required for stimulation of tyrosinase activity.
Abdel-Malek
Z A
ZA
Department of Dermatology, University of Cincinnati College of Medicine, Ohio 45267-0592.
Swope
V B
VB
Trinkle
L S
LS
Nordlund
J J
JJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D004156:Catechol Oxidase / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D016048:Dideoxyadenosine / Q000031:analogs & derivatives*; D015224:Dideoxynucleosides / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D007399:Interphase; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000201:enzymology*; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D015224:Dideoxynucleosides; D016048:Dideoxyadenosine; D003994:Bucladesine; D009074:Melanocyte-Stimulating Hormones; C021008:2',5'-dideoxyadenosine; D000242:Cyclic AMP; D004156:Catechol Oxidase; D014442:Monophenol Monooxygenase; D000527:Alprostadil; D015232:Dinoprostone; D015056:1-Methyl-3-isobutylxanthine