Berberine sensitizes TRAIL-induced apoptosis through proteasome-mediated downregulation of c-FLIP and Mcl-1 proteins
Berberine sensitizes TRAIL-induced apoptosis through proteasome-mediated downregulation of c-FLIP and Mcl-1 proteins
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DOI：
10.3892/ijo.2010.878
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发表时间：
2011-02-01
影响因子：
5.2
通讯作者：
Lee, Tae-Jin
中科院分区：
文献类型：
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作者：
Lee, Sung-Jun;Noh, Hyo-Jeong;Lee, Tae-Jin
黄连素(berberine，BBR)是一种异喹啉生物碱，具有广泛的临床应用，包括抗肿瘤、抗微生物和抗炎活性。在这项研究中，我们发现亚毒性剂量的BBR和肿瘤坏死因子相关的凋亡诱导配体(TRAIL)共同作用于人肾癌细胞Caki细胞，但不能诱导正常肾小管上皮细胞的凋亡。BBR处理Caki细胞后，c-Flip和Mcl-1蛋白表达下调，且呈剂量依赖性。BBR诱导的c-flip和Mcl-1蛋白表达下调参与了蛋白酶体依赖途径，蛋白酶体抑制剂MG 132的预处理可抑制黄连素诱导的c-flip和Mcl-1蛋白表达下调。N-乙酰-L-半胱氨酸(NAC)可明显抑制BBR和TRAIL联合作用所致的细胞死亡，并恢复BBR下调的c-flip和Mcl-1的表达水平。这些结果表明，BBR刺激的TRAIL诱导的细胞凋亡依赖于通过下调c-flip和Mcl-1蛋白而产生的活性氧。综上所述，本研究表明BBR通过ROS介导的c-Flip和Mel-1下调增强TRAIL诱导的人肾癌细胞的凋亡。
Berberine (BBR) is an isoquinoline alkaloid which has a wide spectrum of clinical applications including antitumor, anti-microbial and anti-inflammatory activities. In this study, we showed that co-treatment with subtoxic doses of BBR and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis in human renal cancer cells, Caki cells, but not in normal tubular kidney cells. Treatment of Caki cells with BBR resulted in downregulation of c-FLIP and Mcl-1 proteins in a dose-dependent manner. The BBR-induced downregulation of c-FLIP and Mcl-1 proteins were involved in proteasome dependent pathways, which was confirmed by the result that pre-treatment with the proteasome inhibitor MG 132 inhibited berberine-induced downregulation of the c-FLIP and Mcl-1 proteins. Pretreatment with N-acetyl-l-cysteine (NAC) significantly inhibited the cell death induced by the combined treatment with BBR and TRAIL as well as recovered the expression levels of c-FLIP and Mcl-1 downregulated by treatment with BBR. These results suggested that BBR-stimulated TRAIL-induced apoptosis is dependent on the generation of reactive oxygen species through the downregulation of c-FLIP and Mcl-1 proteins. In conclusion, this study demonstrates that BBR enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated c-FLIP and Mel-1 downregulation.