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.
Highlights
Radiotherapy is a mainstay of cancer therapy in multiple disease contexts, but treatment is not always curative
We derived squamous cell carcinoma (SCC) cells from chemically-induced squamous cell cancers in mice that expressed a floxed form of the ATP-binding coding exon of fak under the control of skin-specific (K14) Cre recombinase fused to the estrogen-receptor [25]
Excision of floxedfak upon a single treatment with 4-hydroxy-tamoxifen (4-OHT) resulted in complete Focal adhesion kinase (FAK) protein deficiency [29,30], which we could reverse by re-expressing wt FAK, allowing us to study how cancer cells cope with severe perturbation of the integrin/FAK signalling pathway
Summary
Radiotherapy is a mainstay of cancer therapy in multiple disease contexts, but treatment is not always curative. A great deal of effort is directed at improving the delivery of radiotherapy by increasingly sophisticated spatial and dosimetric methods, and to identify combination strategies to improve radiation responses In regard of the latter, ionizing radiation can promote activation of receptor and non-receptor tyrosine kinases (TKs), and modulation of cytoprotective influences, such as increased DNA repair, proliferation and reduced apoptosis [1,2,3,4,5,6,7]. Strong preclinical evidence implies a capacity of EGFR inhibition to enhance the anti-tumour effects of ionizing radiation, and this has translated into the clinical setting based on results of a Phase III trial in head and neck cancer [8,9] This demonstrates the importance of robust intervention strategies to establish whether particular TKs contribute to cellular radiosensitivity, or to radio-resistance
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