Effect of bortezomib on ER stress and killing of cisplatin-resistant U2OS osteosarcoma cell line.

9566 Background: Proteasome inhibitor bortezomib is a new class of antineoplastic agents. We believe that the conclusion from previous sarcoma trial that bortezomib was not effective in the treatment of sarcomas should not apply to osteosarcoma since the treatment arm including osteosarcoma was prematurely closed because of low accrual rate. We have previously reported that high level of MKP-1 was associated with cisplatin resistance in osteosarcoma cell lines. Since bortezomib has been reported to increase MKP-1 expression, we investigated the effect of bortezomib treatment on cisplatin sensitivity. Methods: U2OS and P16T osteosarcoma cell lines and mouse embryonic fibroblasts (MEFs) derived from target gene knockout (KO) mice of ATF-4, CHOP, IRE-1 and eIF2α and their paired wild type controls were used in this study. Results: Treatment with bortezomib indeed increased MKP-1 level in U2OS osteosarcoma cell line, but increase in cisplatin resistance was not observed, suggesting that increase in MKP-1 alon...