Calyculin A causes sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by ROS-mediated down-regulation of cellular FLICE-inhibiting protein (c-FLIP) and by enhancing death receptor 4 mRNA stabilization

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• 作者：Seon Min Woo (1)
  Kyoung-jin Min (1)
  Taeg Kyu Kwon (1) kwontk@dsmc.or.kr
• 关键词：Calyculin A – ; TRAIL – ; Death receptor – ; c ; FLIP(L) – ; Reactive oxygen species – ; Protein phosphatase
• 刊名：Apoptosis
• 出版年：2012
• 出版时间：November 2012
• 年：2012
• 卷：17
• 期：11
• 页码：1223-1234
• 全文大小：813.5 KB
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• 作者单位：1. Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701 South Korea
• ISSN：1573-675X

文摘

Calyculin A (Cal A) is a serine/threonine phosphatase inhibitor that is capable of inducing apoptosis in cancer cells. In this study, we examined whether Cal A could modulate TRAIL-induced apoptosis in human renal carcinoma-derived Caki cells. Our results show that Cal A is capable of sensitizing Caki cells to TRAIL-induced apoptosis, as well as U2OS human osteosarcoma cells and A549 human lung adenocarcinoma epithelial cells. Cal A increases intracellular ROS production and down-regulates c-FLIP(L) expression. Interestingly, the down-regulation of protein phosphatase 1 (PP1) by PP1 siRNA also reduced c-FLIP(L) expression via reactive oxygen species production. Furthermore, Cal A induced death receptor 4 (DR4) mRNA and protein expression by enhancing DR4 mRNA stability. We also found that PP4 siRNA up-regulated DR4 mRNA and protein expression. Collectively, our results suggest that Cal A could enhance TRAIL-mediated apoptosis via the down-regulation of c-FLIP(L) and the up-regulation of DR4 in human renal cell carcinoma cell line Caki.