Park Eun Jung, Min Kyoung-jin, Choi Kyeong Sook, Kubatka Peter, Kruzliak Peter, Kim Dong Eun, Kwon Taeg Kyu
Department of Immunology, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Department of Biochemistry &Molecular Biology, Ajou University School of Medicine, Suwon, South Korea.
Sci Rep. 2016 Mar 11;6:22921. doi: 10.1038/srep22921.
Chloroquine (CQ), an anti-malarial drug, has immune-modulating activity and lysosomotropic activity. In this study, we investigated CQ sensitizes TRAIL-mediated apoptosis in human renal cancer Caki cells. Combination of CQ and TRAIL significantly induces apoptosis in human renal cancer Caki cells and various human cancer cells, but not in normal mouse kidney cells (TMCK-1) and human mesangial cells (MC). CQ up-regulates DR5 mRNA and protein expression in a dose- and time- dependent manner. Interestingly, CQ regulates DR5 expression through the increased stability in the mRNA and protein of DR5, rather than through the increased transcriptional activity of DR5. Moreover, we found that CQ decreased the expression of Cbl, an E3 ligase of DR5, and knock-down of Cbl markedly enhanced DR5 up-regulation. Other lysosomal inhibitors, including monensin and nigericin, also up-regulated DR5 and sensitized TRAIL-mediated apoptosis. Therefore, this study demonstrates that lysosomal inhibition by CQ may sensitize TRAIL-mediated apoptosis in human renal cancer Caki cells via DR5 up-regulation.
氯喹（CQ）是一种抗疟药物，具有免疫调节活性和溶酶体亲和性活性。在本研究中，我们研究了CQ使人类肾癌Caki细胞对TRAIL介导的凋亡敏感化的情况。CQ与TRAIL联合使用可显著诱导人类肾癌Caki细胞和各种人类癌细胞凋亡，但对正常小鼠肾细胞（TMCK-1）和人系膜细胞（MC）无效。CQ以剂量和时间依赖性方式上调DR5 mRNA和蛋白表达。有趣的是，CQ通过增加DR5 mRNA和蛋白的稳定性来调节DR5表达，而不是通过增加DR5的转录活性。此外，我们发现CQ降低了DR5的E3连接酶Cbl的表达，敲低Cbl可显著增强DR5的上调。其他溶酶体抑制剂，包括莫能菌素和尼日利亚菌素，也上调DR5并使TRAIL介导的凋亡敏感化。因此，本研究表明，CQ对溶酶体的抑制作用可能通过上调DR5使人类肾癌Caki细胞对TRAIL介导的凋亡敏感化。
