title: Murine melanoma cell differentiation and melanogenesis induced by poly(ADP-ribose) polymerase inhibitors.
abstract: Murine melanoma cells treated with the melanocyte-stimulating hormone (MSH) family of peptides undergo differentiation characterized by enhanced melanogenesis and altered morphology. These effects are mediated via the adenylate cyclase-cAMP pathway leading to activation of protein kinase A (PKA). We have discovered that inhibition of a post-translational modification of chromatin proteins, viz. poly(ADP-ribosylation), also induces melanogenesis and differentiation in these cells. A range of competitive inhibitors (benzamide and its derivatives) of the nuclear enzyme poly(ADP-ribose) polymerase (PADPRP; EC 2.4.2.30) was utilized, and their ability to induce melanogenesis reflected their potency as PADPRP inhibitors. These compounds induced melanogenesis at low doses (20 microM-2 mM) which did not affect cell growth or viability. Induction of melanogenesis was not attributable to inhibition of cyclic nucleotide phosphodiesterase by these compounds. MSH treatment caused a transient rise in cAMP levels (up to 200-fold by 5 min and returning to near basal levels by 5 h). It also stimulated PKA activity up to 5-fold, and the temporal kinetics of this activation mirrored the changes in cAMP levels. In comparison, the PADPRP inhibitors had no effect on either of these processes. These data constitute a novel demonstration of a cAMP-independent mechanism for the induction of melanoma cell differentiation, including melanogenesis.
authors.affiliation: Cancer Research Unit, Medical School, University of Newcastle upon Tyne, United Kingdom.
authors.forename: B W
authors.initials: BW
authors.lastname: Durkacz
authors.forename: J
authors.initials: J
authors.lastname: Lunec
authors.forename: H
authors.initials: H
authors.lastname: Grindley
authors.forename: S
authors.initials: S
authors.lastname: Griffin
authors.forename: O
authors.initials: O
authors.lastname: Horner
authors.forename: A
authors.initials: A
authors.lastname: Simm
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D007700:Kinetics; D008543:Melanins / Q000096:biosynthesis*; D009074:Melanocyte-Stimulating Hormones / Q000502:physiology; D008546:Melanoma, Experimental; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D008543:Melanins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C037689:benzamide; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases