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
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Bortezomib has been known as the most promising anti-cancerdrug for multiple myeloma (MM). However, recent studiesreported that not all MM patients respond to bortezomib. Toovercome such a stumbling-block, studies are needed to clarifythe mechanisms of bortezomib resistance. In this study, weestablished a bortezomib-resistant cell line (U266/velR), andexplored its biological characteristics. The U266/velR showedreduced sensitivity to bortezomib, and also showed crossresistanceto the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation,known as stem-like feature, compared to parentalU266 cells. U266/velR showed relatively less inhibitory effectof prosurvival NF-κB signaling by bortezomib. Further analysisof RNA microarray identified genes related to ubiquitinationthat were differentially regulated in U266/velR. Moreover, theexpression level of CD52 in U266 cells was associated withbortezomib response. Our findings provide the basis for developingtherapeutic strategies in bortezomib-resistant relapsed andrefractory MM patients.
Abstract
Bortezomib has been known as the most promising anti-cancerdrug for multiple myeloma (MM). However, recent studiesreported that not all MM patients respond to bortezomib. Toovercome such a stumbling-block, studies are needed to clarifythe mechanisms of bortezomib resistance. In this study, weestablished a bortezomib-resistant cell line (U266/velR), andexplored its biological characteristics. The U266/velR showedreduced sensitivity to bortezomib, and also showed crossresistanceto the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation,known as stem-like feature, compared to parentalU266 cells. U266/velR showed relatively less inhibitory effectof prosurvival NF-κB signaling by bortezomib. Further analysisof RNA microarray identified genes related to ubiquitinationthat were differentially regulated in U266/velR. Moreover, theexpression level of CD52 in U266 cells was associated withbortezomib response. Our findings provide the basis for developingtherapeutic strategies in bortezomib-resistant relapsed andrefractory MM patients.
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