Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma
AbstractHigh 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
Scifeed alert for new publicationsNever miss any articles matching your research from any publisher
- Get alerts for new papers matching your research
- Find out the new papers from selected authors
- Updated daily for 49'000+ journals and 6000+ publishers
- Define your Scifeed now
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.
Toricelli M, Melo FHM, Hunger A, Zanatta D, Strauss BE, Jasiulionis MG. Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma. Cancers. 2017; 9(4):37.Chicago/Turabian Style
Toricelli, Mariana; Melo, Fabiana H.M.; Hunger, Aline; Zanatta, Daniela; Strauss, Bryan E.; Jasiulionis, Miriam G. 2017. "Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma." Cancers 9, no. 4: 37.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.