Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma

Autor(es)

Toricelli, Mariana ; Melo, Fabiana H. M. ; Hunger, Aline ; Zanatta, Daniela ; Strauss, Bryan E. ; Jasiulionis, Miriam G.

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 9, n. 4 APR 2017.
• Citações Web of Science: 9

Resumo

High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and beta 1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics. Timp1 downregulation resulted in decreased anoikis resistance, clonogenicity, dacarbazine resistance, and in vivo tumor growth and lung colonization. In metastatic cells, pAKT(Thr308) is highly expressed, contributing to anoikis resistance. We showed that PDK1(Ser241) and PKC beta IISer660 are activated by Timp1 in different stages of melanoma progression, contributing to colony formation and anoikis resistance. Moreover, simultaneous inhibition of Timp1 and AKT in metastatic cells resulted in more effective anoikis inhibition. Our findings demonstrate that Timp1 promotes cell survival with the participation of PDK1 and PKC in melanoma. In addition, Timp1 and AKT act synergistically to confer anoikis resistance in advanced tumor stages. This study brings new insights about the mechanisms by which Timp1 promotes cell survival in melanoma, and points to novel perspectives for therapeutic approaches. (AU)

• Processo FAPESP: 10/18715-8 - Determinação das vias de sinalização ativadas pelo complexo CD63, Timp1 e B1-integrinas ao longo da gênese do melanoma
• Beneficiário: Mariana Toricelli Pinto
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/13663-0 - Integração de dados de expressão de genes e microRNAs, metiloma e hidroximetiloma de diferentes etapas da progressão do melanoma.
• Beneficiário: Miriam Galvonas Jasiulionis
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/12306-1 - Mecanismos epigenéticos como mediadores da transformação maligna de melanócitos associada a condições sustentadas de estresse
• Beneficiário: Miriam Galvonas Jasiulionis
• Modalidade de apoio: Auxílio à Pesquisa - Regular