Lee Tae-Jin, Lee Jung Tae, Park Jong-Wook, Kwon Taeg Kyu
Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, Republic of Korea.
Biochem Biophys Res Commun. 2006 Dec 29;351(4):1024-30. doi: 10.1016/j.bbrc.2006.10.163. Epub 2006 Nov 7.
We established TRAIL-resistant MDA-231/TR cells from MDA-231 parent cells to understand the mechanism of TRAIL resistance in breast cancer cells. The selected TRAIL-resistant cells were cross-resistant to TNF-alpha/cycloheximide but remained sensitive to DNA-damage drugs such as oxaliplatin and etoposide. The expression levels of death receptors (DR4 and DR5), FADD, cIAP1, cIAP2, and Bcl-2 family were not changed in TRAIL-treated both cells. Significant down-regulation of XIAP and cFLIP was occurred after TRAIL treatment in MDA-231 cells whereas their levels were sustained in MDA-231/TR cells. TRAIL-mediated activation of ERK and JNK were also observed in parent MDA-231 cells but not in MDA-231/TR cells. However, TRAIL-resistant cells showed constitutive activation state after treatment with TRAIL. Pretreatment with PD98059 or transfection of MKK1-DN (dominant negative) expression vector attenuated TRAIL resistance in MDA-231/TR cells. Our findings provide the evidence that the sustained expression level of cFLIP(L) and XIAP protein and constitutive ERK activation may lead to acquired TRAIL resistance in breast cancer cells.
我们从MDA-231亲本细胞中建立了TRAIL抗性的MDA-231/TR细胞，以了解乳腺癌细胞中TRAIL抗性的机制。所选的TRAIL抗性细胞对TNF-α/放线菌酮具有交叉抗性，但对奥沙利铂和依托泊苷等DNA损伤药物仍敏感。在TRAIL处理的两种细胞中，死亡受体（DR4和DR5）、FADD、cIAP1、cIAP2和Bcl-2家族的表达水平均未改变。TRAIL处理后，MDA-231细胞中XIAP和cFLIP显著下调，而在MDA-231/TR细胞中其水平保持不变。在亲本MDA-231细胞中也观察到TRAIL介导的ERK和JNK激活，但在MDA-231/TR细胞中未观察到。然而，TRAIL抗性细胞在用TRAIL处理后显示出组成性激活状态。用PD98059预处理或转染MKK1-DN（显性阴性）表达载体可减弱MDA-231/TR细胞中的TRAIL抗性。我们的研究结果提供了证据，表明cFLIP(L)和XIAP蛋白的持续表达水平以及组成性ERK激活可能导致乳腺癌细胞获得性TRAIL抗性。
