Phorbol ester impairs melanotropin receptor function and stimulates growth of cultured M2R melanoma cells.
We have examined the effects of a biologically active tumor promoting phorbol ester (phorbol 12-myristate, 13-acetate (PMA] which activates protein kinase C (PKC) on melanotropin receptor function and cell growth in the M2R mouse melanoma cell clone. Treatment of M2R cells with PMA resulted in a significant loss of beta-MSH binding. The effect was both time- and concentration-dependent. The inhibition of beta-MSH binding resulted from a decrease (greater than 85%) in active membranal receptors available on the external cell surface and not from either enhanced internalization or change in the binding affinity. Agonist-stimulated cyclic AMP accumulation was profoundly increased in a non-selective manner following short-term incubation (3 h) with PMA. This effect was completely reversed during long-term (72-96 h) incubation with the tumor promoting agent. Long-term culturing of M2R cells with PMA resulted in enhanced (+50%) proliferation of the melanoma cells. This enhancement was blocked by the addition of agents which stimulate the production of cAMP. Hence, phorbol esters are powerful growth promoters in transformed melanocytes and our findings indicate that the effects of melanotropins are selectively impaired during the process of growth promotion.
Gerst
J E
JE
Department of Hormone Research, Weizmann Institute of Science, Rehovot, Israel.
Benezra
M
M
Schimmer
A
A
Salomon
Y
Y
D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D007457:Iodine Radioisotopes; D009074:Melanocyte-Stimulating Hormones / Q000031:analogs & derivatives / Q000378:metabolism; D008545:Melanoma / Q000503:physiopathology*; D051379:Mice; D010703:Phorbol Esters / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D011979:Receptors, Pituitary Hormone / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007457:Iodine Radioisotopes; D010703:Phorbol Esters; D011506:Proteins; D011979:Receptors, Pituitary Hormone; D005576:Colforsin; C029446:MSH receptor; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate