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Abstract
BackgroundBortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy.ResultsThe present study reports the development of I-45-BTZ-R, a bortezomib-resistant cell line, from the bortezomib-sensitive mesothelioma cell line I-45. I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin, 5-fluorouracil, and doxorubicin. Moreover, the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit β5 (PSMB5) as compared to parental I-45 cells. I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity, but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib. Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response (UPR) in the bortezomib-adapted cells, while higher doses induced UPR with concomitant cell death, as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum (ER) stress-related pro-apoptotic protein CHOP. In addition, bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53, Mcl-1S, and noxa in the bortezomib-adapted cells.ConclusionThese results suggest that UPR evasion, together with reduced pro-apoptotic gene induction, accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R.
Highlights
Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent
Our results suggest that unfolded protein response (UPR) evasion together with reduced pro-apoptotic gene induction accounted for bortezomib resistance in this new bortezomib-adapted mesothelioma cell line
Development of the bortezomib-adapted mesothelioma cell line I-45-BTZ-R To determine whether prolonged exposure of the mesothelioma cell line I-45 to bortezomib would select for cells resistant to bortezomib treatment, I-45 cells were exposed to 12 nM bortezomib
Summary
Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. Characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy. Therapeutic targeting of the proteasome pathway with the specific inhibitor bortezomib has been successful in selectively inducing apoptosis in mesothelioma and a variety of other human cancer cells, with tolerable toxicity to normal cells and tissues [2,3,4]. Cancer cell resistance to bortezomib-mediated apoptosis may limit the successful application of bortezomib as a cancer therapeutic agent. Many patients with MM who initially responded to bortezomib relapse with bortezomib-refractory disease [8], suggesting that even in the cancer exhibiting the best treatment response, bortezomib resistance remains a significant obstacle to treatment efficacy
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