title: Establishment and characterization of bortezomib-resistant U266 cell line: constitutive activation of NF-κB-mediated cell signals and/or alterations of ubiquitylation-related genes reduce bortezomib-induced apoptosis.
abstract: Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Juwon
authors.initials: J
authors.lastname: Park
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Seoul 110-799, Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Bae
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Chansu
authors.initials: C
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Jee-Hye
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Woo June
authors.initials: WJ
authors.lastname: Jung
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Seoul 110-799, Korea.
authors.forename: Kwang-Sung
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; C508241:SDC1 protein, human; D053668:Syndecan-1; D013792:Thalidomide; D000069286:Bortezomib