Investigation of resistance mechanisms to TRAIL in advanced prostate cancer cell lines

Title of Thesis: Investigation of Resistance Mechanisms to TRAIL in Advanced ProstateCancer Cell LinesAuthor: Ahter Dilşad ŞANLIOĞLUABSTRACTAdenovirus-mediated gene therapy approaches using TRAIL arose as powerfulpotential therapy modalities in advanced prostate carcinoma. However, as TRAILresistance was reported in some prostate cancer cells, investigation of resistancemechanisms to TRAIL in advanced prostate carcinoma cells and development of newtherapeutic approaches are crucial for TRAIL to be used efficiently in clinical settings inthe future.For this reason, unstimulated and TRAIL-induced NF-kB activities and TRAILdeath and decoy receptor patterns were investigated as possible resistance mechanisms toTRAIL in three different advanced prostate carcinoma cell lines (DU145, PC3, LNCaP).Furthermore, efficiency of a dual vector approach including Ad5hTRAIL andAdIKKbetaKA in breaking down the TRAIL resistance in cells was investigated.Our results revealed that TRAIL decoy receptor composition and intracellular NF-kB activity are two important factors leading to TRAIL resistance in advanced prostatecancer cells. Furthermore, IKKbetaKA-mediated IKK inhibiting strategies were efficientin breaking down the resistance to TRAIL in cells independent of the resistancemechanisms. Our investigation has shown a significant correlation between decoyreceptor expression levels and TRAIL resistance in advanced prostate cancer cells.Furthermore, this is the first study showing that a dual vector strategy with Ad5hTRAILand AdIKKbetaKA is efficient in eliminating TRAIL resistance in advanced prostatecancer cells. Consequently, this dual vector approach appears to be a novel potentialtreatment modality to increase the theraupetic index of TRAIL in advanced prostatecancers.Key Words: TRAIL, prostate cancer, gene therapy, NF-kB, adenoviral vectors.