title: FAK deletion promotes p53-mediated induction of p21, DNA-damage responses and radio-resistance in advanced squamous cancer cells.
abstract: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is elevated in a variety of human cancers. While FAK is implicated in many cellular processes that are perturbed in cancer, including proliferation, actin and adhesion dynamics, polarisation and invasion, there is only some limited information regarding the role of FAK in radiation survival. We have evaluated whether FAK is a general radio-sensitising target, as has been suggested by previous reports. We used a clean genetic system in which FAK was deleted from mouse squamous cell carcinoma (SCC) cells (FAK -/-), and reconstituted with exogenous FAK wild type (wt). Surprisingly, the absence of FAK was associated with increased radio-resistance in advanced SCC cells. FAK re-expression inhibited p53-mediated transcriptional up-regulation of p21, and a sub-set of other p53 target genes involved in DNA repair, after treatment with ionizing radiation. Moreover, p21 depletion promoted radio-sensitisation, implying that FAK-mediated inhibition of p21 induction is responsible for the relative radio-sensitivity of FAK-proficient SCC cells. Our work adds to a growing body of evidence that there is a close functional relationship between integrin/FAK signalling and the p53/p21 pathway, but demonstrates that FAK's role in survival after stress is context-dependent, at least in cancer cells. We suggest that there should be caution when considering inhibiting FAK in combination with radiation, as this may not always be clinically advantageous.
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, Scotland.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Graham
authors.forename: Kim
authors.initials: K
authors.lastname: Moran-Jones
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D009367:Neoplasm Staging; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D051416:Focal Adhesion Protein-Tyrosine Kinases