OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Insulin-like growth factors (IGFs) activate multiple signalling pathways. It has been suggested, they prevent apoptosis via activation of phosphoinositide 3-kinase-Akt. The role of IGF-1 in OSCC is unknown but the gene encoding downstream effector PI3K, PI3K3CA, is amplified in this cancer type. The aim was to study effects of IGF-1 in the protection against cell apoptosis in transformed gingival keratinocytes and to inhibit the PI3K/Akt signalling pathway.This may be of interest in oral cancer treatment. METHODS: Apoptosis of neoplastic gingival keratinocytes (FIBS) was induced by staurosporine (1.5-15nM) and cisplatin (1.6-8microM). Cell viability was monitored for 24h using alamar Blue and MTT assays. Supernatants were tested for LDH leakage. As a measure of apoptosis, caspase 3/7 activity was measured using a commercial fluorimetric assay following various treatments of the cells with IGF-1 and drugs. Inhibitors of the PI3 kinase (LY-294002) and Akt were also studied with relation to the caspase activity. RESULTS: Cell viability decreased as concentrations of both staurosporine and cisplatin increased. The higher concentrations of the drugs induced greater caspase activity, which were also time dependant, 24h treatment with 1.6microM cisplatin and 1.5nM staurosporine showed the significant caspase activity. However, when cells were treated with 10nM IGF-1 in combination with either 1.5 nM staurosporine or 1.6microM cisplatin, no change in viability was observed and caspase activity was suppressed. CONCLUSIONS: The chemotherapeutic drugs decreased cell viability and induced executioner caspase activity in the FIBS, diagnostic of apoptosis. However, based on our results, the ubiquitous presence of IGF-1 in vivo could have a protective effect on the cells treated with the drugs. Inhibition of downstream signalling effector molecules, PI3K and Akt, represses its defensive mechanism underling these kinase as targets for drug development in OSCC.
Pan European Federation Meeting
2006 Pan European Federation Meeting (Dublin, Ireland) Dublin, Ireland
2006 184 Scientific Groups
Damerau, Richard
( Centre of Clinical and Diagnostic Oral Sciences,Bart's and The London Queen Mary University of London, London, N/A, United Kingdom
)
Collier, Jonathan Marc
( Queen Mary University, London, N/A, United Kingdom
)
Parkinson, E. K.
( Centre of Clinical and Diagnostic Oral Sciences,Bart's and The London Queen Mary University of London, London, N/A, United Kingdom
)