Park Juwon, Bae Eun-Kyung, Lee Chansu, Choi Jee-Hye, Jung Woo June, Ahn Kwang-Sung, Yoon Sung-Soo
Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
Biomedical Research Institute, Seoul National University Hospital, Seoul 110-799, Korea.
BMB Rep. 2014 May;47(5):274-9. doi: 10.5483/bmbrep.2014.47.5.134.
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.
硼替佐米已被公认为是治疗多发性骨髓瘤（MM）最有前景的抗癌药物。然而，最近的研究报告称，并非所有MM患者都对硼替佐米有反应。为了克服这一障碍，需要开展研究以阐明硼替佐米耐药的机制。在本研究中，我们建立了硼替佐米耐药细胞系（U266/velR），并探究了其生物学特性。U266/velR对硼替佐米的敏感性降低，并且对化学结构不相关的药物沙利度胺也表现出交叉耐药性。与亲代U266细胞相比，U266/velR细胞具有更高比例的CD138阴性亚群，这是一种干细胞样特征。U266/velR对硼替佐米介导的促生存NF-κB信号传导的抑制作用相对较小。RNA微阵列的进一步分析鉴定出在U266/velR中差异调节的与泛素化相关的基因。此外，U266细胞中CD52的表达水平与硼替佐米反应相关。我们的研究结果为制定硼替佐米耐药复发难治性MM患者的治疗策略提供了依据。
