| dc.description.abstract | Squamous cell carcinomas (SCCs) of the aerodigestive tract often recur because of incomplete excision or the appearance of second primary or second field cancers. Recent evidence suggests that the omega-3 polyunsaturated fatty acids (PUFA) have antitumorigenic activities. In the present study the potential of omega-3 PUFA to act as selective chemopreventive and therapeutic agents against oral and epidermal SCCs was tested and the mechanism of action was investigated. The effect of omega-3-PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on oral and epidermal malignant SCC and pre-malignant cell lines and also normal keratinocytes were examined. The PUFA inhibited growth dose-dependently after 4 days, as measured by MTT cell viability assays. The PUFA appeared to be more selective against malignant and premalignant than normal keratinocytes. It was demonstrated that PUFA caused apoptosis by the annexin V apoptosis assay and cleavage of caspase 3 by western blotting. The cleavage of caspase 9 and 8 demonstrated the involvement of the intrinsic and extrinsic apoptotic pathways, respectively. Moreover, DHA and EPA decreased cell proliferation by the 3H-thymidine uptake assay. PUFA appeared to increase ROS production and DNA damage after 16 hours, especially at the higher concentrations. However, the use of anti-oxidants could not rescue the cell. Furthermore, the role of telomerase in PUFA mechanism of action was not confirmed as overexpression of TERT, TERT-HA and CMYC did not protect the cells from the growth inhibitory effect of PUFA and serum albumin was identified as an antagonist of PUFA inhibitory effect. PUFA caused a rapid and sustained phosphorylation of ERK1/2 which is inhibited by MEK and EGF receptor inhibitors. The phosphorylation of ERK1/2 was accompanied by an increase in COX-2 expression. An increase in the phosphorylation of JNK, especially in higher doses, but no effect on Akt phosphorylation, was observed. It is hypothesised that PUFA may secrete a ligand which causes the suprastimulation of EGFR and over-activation of ERK1/2 pathway which leads to apoptosis. In summary, the omega-3-PUFA DHA and EPA display a marked anti-tumour effect against SCC keratinocytes at concentrations that do not eliminate normal cells, thus giving them a significant potential as future therapeutic and prophylactic tools against head and neck cancer. | en_US |
