Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2012 May 25;422(1):42-7. doi: 10.1016/j.bbrc.2012.04.093. Epub 2012 Apr 25.
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. However, tumor cells often develop resistance to TRAIL, limiting its therapeutic potential. To study the mechanism underlying TRAIL-resistance in breast cancer cells, we performed a high-throughput compound screen in MCF-7 cells. We identified daunorubicin as a potent sensitizer of TRAIL-induced apoptosis in MCF-7 cells. Daunorubicin in combination with subtoxic concentrations of recombinant human TRAIL induced massive apoptosis in MCF-7 cells. This combination was effective in TRAIL-resistant MDA-MB-231 and T47D breast cancer cells. By immunoblotting, we found that daunorubicin treatment induced loss of the anti-apoptotic protein, Mcl-1, in breast cancer cells. RNA interference experiments revealed that reduced expression of Mcl-1 sensitized MCF-7 cells to TRAIL. Together, these data suggest that Mcl-1 is a major contributor to TRAIL-resistance in breast cancer cells, and that reduction of Mcl-1 protein levels using DNA damaging agents is a promising approach for cancer therapy.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种很有前途的癌症治疗药物。然而，肿瘤细胞常常对 TRAIL 产生耐药性，限制了其治疗潜力。为了研究乳腺癌细胞中 TRAIL 耐药的机制，我们在 MCF-7 细胞中进行了高通量化合物筛选。我们发现柔红霉素是 MCF-7 细胞中 TRAIL 诱导凋亡的有效增敏剂。柔红霉素与亚毒性浓度的重组人 TRAIL 联合使用可诱导 MCF-7 细胞发生大量凋亡。该联合方案对 TRAIL 耐药的 MDA-MB-231 和 T47D 乳腺癌细胞有效。通过免疫印迹，我们发现柔红霉素处理诱导乳腺癌细胞中抗凋亡蛋白 Mcl-1 的丢失。RNA 干扰实验表明，Mcl-1 的表达降低使 MCF-7 细胞对 TRAIL 敏感。综上所述，这些数据表明 Mcl-1 是乳腺癌细胞中 TRAIL 耐药的主要贡献者，使用 DNA 损伤剂降低 Mcl-1 蛋白水平是癌症治疗的一种很有前途的方法。
