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咖啡二萜卡维醇通过下调Mcl-1和c-FLIP的表达增强人肾癌Caki细胞对索拉非尼的敏感性。

The coffee diterpene kahweol enhances sensitivity to sorafenib in human renal carcinoma Caki cells through down-regulation of Mcl-1 and c-FLIP expression.

作者信息

Min Kyoung-Jin, Um Hee Jung, Kim Jee In, Kwon Taeg Kyu

机构信息

Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, South Korea.

Department of Molecular Medicine, School of Medicine, Keimyung University, Daegu 704-701, South Korea.

出版信息

Oncotarget. 2017 Aug 24;8(47):83195-83206. doi: 10.18632/oncotarget.20541. eCollection 2017 Oct 10.

DOI:10.18632/oncotarget.20541
PMID:29137334
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5669960/
Abstract

Sorafenib is approved for the treatment of hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). However, low tumor response and side effects have been widely reported. Therefore, to improve the efficacy of sorafenib, we investigated whether combined treatment with sorafenib and kahweol, the coffee-specific diterpene, has a synergistic effect on apoptotic cell death. Combined treatment with sorafenib and kahweol markedly induced caspase-mediated apoptosis in renal carcinoma Caki cells. Combined treatment with sorafenib and kahweol induced down-regulation of Mcl-1 and c-FLIP expression. We found down-regulation of Mcl-1 and c-FLIP expression was modulated by the ubiquitin-proteasome pathway. Ectopic expression of Mcl-1 inhibited sorafenib plus kahweol-induced apoptosis. Interestingly, combined treatment with sorafenib and kahweol induced apoptotic cell death in c-FLIP overexpressed cells. In addition, combined treatment with sorafenib and kahweol markedly induced apoptosis in human lung carcinoma (A549) and breast carcinoma (MDA-MB-361) cells, but not in human normal mesangial cells and human skin fibroblast cells (HSF). Collectively, our study demonstrates that combined treatment with sorafenib and kahweol induces apoptotic cell death through down-regulation of Mcl-1 expression.

摘要

索拉非尼被批准用于治疗肝细胞癌（HCC）和晚期肾细胞癌（RCC）。然而，肿瘤反应率低和副作用已被广泛报道。因此，为了提高索拉非尼的疗效，我们研究了索拉非尼与咖啡特有的二萜卡维醇联合治疗是否对凋亡性细胞死亡具有协同作用。索拉非尼与卡维醇联合治疗显著诱导肾癌细胞Caki细胞中半胱天冬酶介导的凋亡。索拉非尼与卡维醇联合治疗诱导Mcl-1和c-FLIP表达下调。我们发现Mcl-1和c-FLIP表达的下调是由泛素-蛋白酶体途径调节的。Mcl-1的异位表达抑制了索拉非尼加卡维醇诱导的凋亡。有趣的是，索拉非尼与卡维醇联合治疗在c-FLIP过表达的细胞中诱导凋亡性细胞死亡。此外，索拉非尼与卡维醇联合治疗显著诱导人肺癌（A549）和乳腺癌（MDA-MB-361）细胞凋亡，但对人正常系膜细胞和人皮肤成纤维细胞（HSF）无此作用。总体而言，我们的研究表明，索拉非尼与卡维醇联合治疗通过下调Mcl-1表达诱导凋亡性细胞死亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/017d508e53b9/oncotarget-08-83195-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/127adf8786ad/oncotarget-08-83195-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/df294a91ba5d/oncotarget-08-83195-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/b05c620f27fc/oncotarget-08-83195-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/f7e9a4e5fe61/oncotarget-08-83195-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/22972db6b4d2/oncotarget-08-83195-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/017d508e53b9/oncotarget-08-83195-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/127adf8786ad/oncotarget-08-83195-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/df294a91ba5d/oncotarget-08-83195-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/b05c620f27fc/oncotarget-08-83195-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/f7e9a4e5fe61/oncotarget-08-83195-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/22972db6b4d2/oncotarget-08-83195-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/5669960/017d508e53b9/oncotarget-08-83195-g006.jpg

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