Characterization of bortezomib-adapted I-45 mesothelioma cells

Molecular Cancer

Research

James E Littlejohn¹  W Roy Smythe¹  Chander Peddaboina¹  Xiaobo Cao¹  Lidong Zhang¹  Yu Cui² 

[1] Section of Surgery Research, Department of Surgery, Texas A & M University Health Science Center College of Medicine and Scott & White Memorial Hospital, Temple, Texas, USA;Section of Surgery Research, Department of Surgery, Texas A & M University Health Science Center College of Medicine and Scott & White Memorial Hospital, Temple, Texas, USA;Department of Oncology, Tianjin Union Medicine Center, Tianjin, China;

关键词: Endoplasmic Reticulum Stress;    Bortezomib;    Unfold Protein Response;    Proteasome Activity;    Ubiquitinated Protein;   

DOI  :  10.1186/1476-4598-9-110

 received in 2009-11-19, accepted in 2010-05-18,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Zhang et al; licensee BioMed Central Ltd. 2010