Integrin-Dependent Cell Growth and Survival Are Mediated by Different Signals in Thyroid Cells
Maddalena Illario,
Virginia Amideo,
Adele Casamassima,
Michele Andreucci,
Tiziana di Matola,
Claudia Miele,
Guido Rossi,
Gianfranco Fenzi and
Mario Vitale
Dipartimento di Biologia e Patologia Cellulare e Molecolare (M.I., V.A., A.C., T.D.M., G.R., M.V.), Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (G.F.), e Cattedra di Nefrologia (M.A.), Università Federico II, 80131 Naples, Italy; and Centro di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" (C.M., G.R.), Consiglio Nazionale delle Ricerche, 80131 Naples, Italy
Address all correspondence and requests for reprints to: Mario Vitale, M.D., Dipartimento di Biologia e Patologia Cellulare e Molecolare, Via S. Pansini 5, 80131 Napoli, Italy. E-mail: mavitale{at}unina.it.
Cell adhesion to extracellular matrix regulates proliferationand survival of several cell types including epithelial thyroidcells. Activation of integrin receptors by binding to extracellularmatrix generates a complex cell type-dependent signaling. Adhesionto extracellular matrix induces proliferation and survival inprimary cultures of thyroid cells and induces survival in immortalizedhuman thyrocytes. In this study we demonstrate that in immortalizedhuman thyrocyte cells, adhesion to immobilized fibronectin (FN)stimulates DNA synthesis and proliferation through the p21Ras/MAPKpathway, whereas cell survival is mediated by phosphatidylinositol3-kinase (PI3K) signal pathway. Integrin activation by immobilizedFN induced phosphorylation of pp125 focal adhesion kinase andpaxillin and induced the formation of focal adhesion kinase/Grb-2/Soscomplex. Western blot and in vitro kinase assay demonstratedthe activation of Ras and the p44/p42 MAPK/ERK1/2. Inhibitionof p21Ras activity and inhibition of MAPK enzymatic activitycompletely arrested cell growth but did not induce cell death.Integrin activation by cell adhesion to FN also induced activationof PI3K. Inhibition of PI3K enzymatic activity induced apoptosisdemonstrated by annexin V-binding assay and loss of cellularDNA content. These results demonstrate that in thyroid cellsadhesion to FN regulates proliferation through the p21Ras/MAPKsignal pathway, whereas integrin-mediated cell survival is mediatedby PI3K.
This work was partly supported by Ministero dell’Universitàe della Ricerca Scientifica (to G.F.), Consiglio Nazionale delleRicerche (CNR; to M.V.), and Fondazione Italiana per la Ricercasul Cancro (FIRC; to T.D.M.).
Y. Zheng, J. D. Ritzenthaler, J. Roman, and S. Han Nicotine Stimulates Human Lung Cancer Cell Growth by Inducing Fibronectin Expression
Am. J. Respir. Cell Mol. Biol.,
December 1, 2007;
37(6):
681 - 690.
[Abstract][Full Text][PDF]
K. Fujarewicz, M. Jarzab, M. Eszlinger, K. Krohn, R. Paschke, M. Oczko-Wojciechowska, M. Wiench, A. Kukulska, B. Jarzab, and A. Swierniak A multi-gene approach to differentiate papillary thyroid carcinoma from benign lesions: gene selection using support vector machines with bootstrapping
Endocr. Relat. Cancer,
September 1, 2007;
14(3):
809 - 826.
[Abstract][Full Text][PDF]
M. Illario, A. L. Cavallo, S. Monaco, E. Di Vito, F. Mueller, L. A. Marzano, G. Troncone, G. Fenzi, G. Rossi, and M. Vitale Fibronectin-Induced Proliferation in Thyroid Cells Is Mediated by {alpha}v{beta}3 Integrin through Ras/Raf-1/MEK/ERK and Calcium/CaMKII Signals
J. Clin. Endocrinol. Metab.,
May 1, 2005;
90(5):
2865 - 2873.
[Abstract][Full Text][PDF]
A. Marconi, P. Atzei, C. Panza, C. Fila, R. Tiberio, F. Truzzi, T. Wachter, M. Leverkus, and C. Pincelli FLICE/caspase-8 activation triggers anoikis induced by {beta}1-integrin blockade in human keratinocytes
J. Cell Sci.,
November 15, 2004;
117(24):
5815 - 5823.
[Abstract][Full Text][PDF]
M. Illario, A. L. Cavallo, K. U. Bayer, T. Di Matola, G. Fenzi, G. Rossi, and M. Vitale Calcium/Calmodulin-dependent Protein Kinase II Binds to Raf-1 and Modulates Integrin-stimulated ERK Activation
J. Biol. Chem.,
November 14, 2003;
278(46):
45101 - 45108.
[Abstract][Full Text][PDF]
