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

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dc.citation.issue4
dc.citation.volume9
dc.contributor.authorToricelli, Mariana [UNIFESP]
dc.contributor.authorMelo, Fabiana H. M. [UNIFESP]
dc.contributor.authorHunger, Aline
dc.contributor.authorZanatta, Daniela
dc.contributor.authorStrauss, Bryan E.
dc.contributor.authorJasiulionis, Miriam G. [UNIFESP]
dc.coverageBasel
dc.date.accessioned2020-07-17T14:02:23Z
dc.date.available2020-07-17T14:02:23Z
dc.date.issued2017
dc.description.abstractHigh 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.en
dc.description.affiliationUniv Fed Sao Paulo, Dept Pharmacol, BR-04039032 Sao Paulo, Brazil
dc.description.affiliationUniv Sao Paulo, Sch Med, Canc Inst Sao Paulo, Ctr Translat Invest Oncol LIM 24, BR-01246000 Sao Paulo, Brazil
dc.description.affiliationFac Med Santa Casa Sao Paulo, BR-01221020 Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Pharmacol, BR-04039032 Sao Paulo, Brazil|
dc.description.sourceWeb of Science
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico
dc.description.sponsorshipIDFAPESP: 2010/18715-8
dc.description.sponsorshipIDFAPESP: 2011/12306-1
dc.description.sponsorshipIDFAPESP: 2014/13663-0
dc.description.sponsorshipIDCNPq: 470681/2012-8
dc.format.extent-
dc.identifierhttp://dx.doi.org/10.3390/cancers9040037
dc.identifier.citationCancers. Basel, v. 9, n. 4, p. -, 2017.
dc.identifier.doi10.3390/cancers9040037
dc.identifier.fileWOS000404373000011.pdf
dc.identifier.issn2072-6694
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/54780
dc.identifier.wosWOS:000404373000011
dc.language.isoeng
dc.publisherMdpi Ag
dc.relation.ispartofCancers
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectTimp1en
dc.subjectanoikis resistanceen
dc.subjectPI3K pathwayen
dc.subjectPDK1en
dc.subjectPKCen
dc.subjectmelanomaen
dc.titleTimp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanomaen
dc.typeinfo:eu-repo/semantics/article
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