title: Guanosine promotes B16F10 melanoma cell differentiation through PKC-ERK 1/2 pathway.
abstract: Malignant melanoma is one of the most lethal cancers. Nowadays, several anti-melanoma therapies have been employed. However, the poor prognosis and/or the increased toxicity of those treatments clearly demonstrate the requirement of searching for new drugs or novel combined chemotherapeutic protocols, contemplating both effectiveness and low toxicity. Guanosine (Guo) has been used in combination with acriflavina to potentiate the latter's antitumor activity, through still unknown mechanisms. Here, we show that Guo induces B16F10 melanoma cell differentiation, attested by growth arrest, dendrite-like outgrowth and increased melanogenesis, and also reduced motility. A sustained ERK 1/2 phosphorylation was observed after Guo treatment and ERK inhibition led to blockage of dendritogenesis. Intracellular cyclic AMP was not involved in ERK activation, since its levels remained unchanged. Protein kinase C (PKC), in contrast to phospholipase C (PLC), inhibition completely prevented ERK activation. While the classical melanoma differentiation agent forskolin activates cAMP-PKA-Raf-MEK-ERK pathway in B16F10 cells, here we suggest that a cAMP-independent, PKC-ERK axis is involved in Guo-induced B16F10 differentiation. Altogether, our results show that Guo acts as a differentiating agent, with cytostatic rather than cytotoxic properties, leading to a decreased melanoma malignancy. Thus, we propose that Guo may be envisaged in combination with lower doses of conventional anti-melanoma drugs, in an attempt to prevent or diminish their adverse effects.
authors.affiliation: Department of Basic Pathology, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: Katya
authors.initials: K
authors.lastname: Naliwaiko
authors.forename: Aline C
authors.initials: AC
authors.lastname: Luvizon
authors.forename: Lucélia
authors.initials: L
authors.lastname: Donatti
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.forename: Adriana F
authors.initials: AF
authors.lastname: Mercadante
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Zanata
authors.forename: Lia S
authors.initials: LS
authors.lastname: Nakao
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006151:Guanosine / Q000494:pharmacology*; D006801:Humans; D008543:Melanins / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: D008543:Melanins; D006151:Guanosine; D000242:Cyclic AMP; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases