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Identifier

000390015

Title

Quantitative changes in Focal Adhesion Kinase (FAK) regulate secretory signaling for cell survival

Alternative Title

Ποσοτικές αλλαγές στην Κινάση Εστιακής Προσκόλλησης (FAK) ρυθμίζουν εκκριτικά σηματοδοτικά μονοπάτια που μεσολαβούν στην κυτταρική επιβίωση

Author

Γιαλεσάκη Σοφία

Thesis advisor

Ηλιόπουλος, Α.

Abstract

Focal adhesion kinase (FAK) is a major component of the integrin-linked focal contacts and is implicated in a variety of physiological cellular functions including motility, invasion and anoikis. Whilst FAK overexpression is a feature of various tumor types and contributes to carcinogenic processes, genetic studies in mice demonstrate that FAK-depleted epithelial cells remain susceptible to malignant transformation through mechanisms which remain ill-defined. In our project, we demonstrate that silencing or inactivation of FAK in tumor cells downregulates TNFα-induced signaling pathways, resulting in decreased secretion of IL6 and impaired phosphorylation of ERK1/2. The knock down of FAK, using small interfering RNAs (siRNAs), in cervical (HeLa) and lung cancer (A549) cell lines leads to basal level production of IL6 and STAT3 phosphorylation to normal levels. Inhibition of FAK activity, using the pharmacological FAK inhibitor PF-573,228, results in a slight decrease in both secreted IL6 and pSTAT3 levels. TNFα is known to induce IL6 expression and secretion, as well as ERK1/2 phosphorylation via NFκB-dependent signaling pathways. Treatment of FAK depleted cells with TNFα results in reduced IL6 mRNA and protein levels, as well as to decreased ERK1/2 phosphorylation. FAK activity inhibition also leads to reduced pERK1/2 levels, even upon TNFα treatment. However, the loss of TNFα-induced ERK signaling might be NFκB-independent because IκBα degradation is unaltered in case of treatment with the FAK inhibitor. Our results further support the already known functions of FAK and indicate therapeutic opportunities by targeting specific aspects of FAK signal transduction.

Language

English

Subject

Focal Adhesion kinase(FAK)

Nuclear factor Kappa B(NFkB)

Small interfering RNA

Κινάση εστιακής προσκόλλησης(FAK)

Μικρά παρεμβαλλόμενα RNA(siRNA)

Issue date

2014-12-04

Collection

School/Department--School of Medicine--Department of Medicine--Post-graduate theses