Proteasome inhibitor bortezomib is a novel anticancer drug that has exhibited strong antitumor activity against a wide range of malignancies. However, resistance to bortezomib may impede clinical use of this agent. In this study, to characterize mechanisms of bortezomib resistance and further develop strategies to overcome it, we developed a bortezomib-resistant cell line by repeated treatment of mesothelioma cell line I-45 with gradually increased concentrations of bortezomib (10-100 nM) and name it I-45-R cells. Continuous exposure to 50 nM bortezomib for three days, the cell viability in parental I-45 cells was below 12 %, while the cell viability in I-45-R cells was over 83 %. Compared with I-45 cells, I-45-R cells did not show significant bortezomib-mediated G2/M phase arrest. Autophagy did not account for bortezomib resistance, as I-45-R cells did not show the conversion of LC3 to the lower migrating form LC3-II in response to bortezomib treatment. Subsequent study showed that greatly accumulated ubiquitinated proteins including p53 were observed only in the parental I-45 cells, but not in the I-45-R cells after treatment with bortezomib. In addition, compared with parental I-45 cells, our study also showed significantly reduced accumulation of BH3-only pro-apoptotic protein NOXA in I-45-R cells. Our results suggest that incapability of accumulation of bortezomib-mediated polyubiquitinated proteins in I-45-R cells may reduce expression of key apoptosis-related genes, such as p53 and NOXA, thus leading to bortezomib resistance.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-206.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009