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Cancers 2017, 9(4), 37;

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

Pharmacology Department, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil
Center for Translational Investigation in Oncology/LIM 24, Cancer Institute of São Paulo, School of Medicine, University of São Paulo, São Paulo 01246-000, Brazil
Current address: Faculdade de Medicina da Santa Casa de São Paulo, São Paulo 01221-020, Brazil
Author to whom correspondence should be addressed.
Academic Editor: Marco Falasca
Received: 14 February 2017 / Revised: 12 April 2017 / Accepted: 14 April 2017 / Published: 21 April 2017
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and β1 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, pAKTThr308 is highly expressed, contributing to anoikis resistance. We showed that PDK1Ser241 and PKCβIISer660 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. View Full-Text
Keywords: Timp1; anoikis resistance; PI3K pathway; PDK1; PKC; melanoma Timp1; anoikis resistance; PI3K pathway; PDK1; PKC; melanoma

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Toricelli, M.; Melo, F.H.M.; Hunger, A.; Zanatta, D.; Strauss, B.E.; Jasiulionis, M.G. Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma. Cancers 2017, 9, 37.

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