Characterization of bortezomib-adapted I-45 mesothelioma cells.
BACKGROUND
Bortezomib, 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.


RESULTS
The 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 beta5 (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.


CONCLUSIONS
These 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.
Zhang
Lidong
L
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. lidongz@bcm.tmc.edu
Littlejohn
James E
JE
Cui
Yu
Y
Cao
Xiaobo
X
Peddaboina
Chander
C
Smythe
W Roy
WR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D056811:Unfolded Protein Response / Q000187:drug effects*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C539791:Bax-inhibiting peptide, BIP; D001897:Boronic Acids; C497249:DDIT3 protein, human; D009842:Oligopeptides; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex