A58
The Role of c-FLIP in regulating pancreatic cancer cell death
Kelly Redmond, Kirsty McLaughlin, Timothy Wilson, Emma Kerr, Patrick Johnston, Daniel Longley
Queen's University Belfast, Belfast, UK
Background
Despite having a relatively low incidence rate of about 10 cases per 100,000 population, the survival rate for pancreatic cancer is among the lowest for all cancers, with 10% of patients surviving after one year and only 3% of patients after five years. These extremely low survival rates are often due to the high levels of intrinsic drug resistance within the tumours. We have previously shown that c-FLIP is a key regulator of chemotherapy- and death ligand-induced cell death in colorectal cancer.
Aim
The aim of this study was to elucidate the role of c-FLIP in chemotherapy-induced apoptosis in pancreatic cancer cells
Method and results
c-FLIPgene silencing was shown to induce spontaneous apoptosis in a panel of pancreatic cell lines in both a dose- and time-dependent manner. Despite expressing the TRAIL death receptors DR4 and DR5 at the cell surface, these cells are resistant to the death ligand TRAIL. Silencing of c-FLIP led to sensitisation of these cells to TRAIL treatment, as measured by flow cytometry, with the synergistic relationship confirmed by MTT assay and the subsequent calculation of Combination Index values using Calcusyn Software. Furthermore, c-FLIP gene silencing was found to sensitise these cell lines to both cisplatin and gemcitabine treatment. Finally, splice-form specific gene silencing of c-FLIP indicated that both c-FLIP splice variants need to be silenced in order to observe the above phenotypes.
Conclusion
Collectively, our results indicate that c-FLIP is an important mediator of chemoresistance in pancreatic cancer, and that c-FLIP may be an important therapeutic target in the treatment of this disease.
