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

Author(s)

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

• Document type: Journal article
• Source: CANCERS; v. 9, n. 4 APR 2017.
• Web of Science Citations: 9

Abstract

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)

• FAPESP's process: 10/18715-8 - Signaling pathways activated by the complex CD63, B1-integrin and Timp1 along the genesis of melanoma
• Grantee: Mariana Toricelli Pinto
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/13663-0 - Integrating gene and microRNA expression, methylome and hidroxymethylome data from different phases of melanoma progression.
• Grantee: Miriam Galvonas Jasiulionis
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/12306-1 - Epigenetic mechanisms as mediators of melanocyte malignant transformation associated with sustained stress condition
• Grantee: Miriam Galvonas Jasiulionis
• Support Opportunities: Regular Research Grants