Fenretinide upregulates DR 5 / TRAIL-R 2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines
Fenretinide upregulates DR 5 / TRAIL-R 2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines
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发表时间：
2007
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通讯作者：
J. Kouhara;Tatsushi Yoshida;Susumu Nakata;Mano Horinaka;Miki Wakada;Y. Ueda;H. Yamagishi;T. Sakai
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作者：
J. Kouhara;Tatsushi Yoshida;Susumu Nakata;Mano Horinaka;Miki Wakada;Y. Ueda;H. Yamagishi;T. Sakai
芬维A胺（N-[4-羟基苯基]维A酰胺; 4 HPR）是一种半合成类维生素A，可诱导多种恶性肿瘤细胞凋亡。芬维A胺已在临床试验中作为癌症化学预防剂和化学治疗剂进行了检查。已显示芬维A胺诱导的氧化应激通过诱导转录因子CCAAT/增强子结合蛋白同源蛋白（CHOP）和巴克通过线粒体途径介导细胞凋亡。在这项研究中，我们报告，芬维A胺诱导死亡受体5（DR 5）/TRAIL-R2的上调，通过诱导转录因子CHOP在结肠癌细胞系。芬维A胺在蛋白和mRNA水平诱导DR 5表达。此外，芬维A胺增加DR 5启动子的活性和增强的活性下降的突变的CHOP结合位点。芬维A胺也在启动子水平上调CHOP。我们还表明，芬维A胺和TRAIL的联合治疗诱导结肠癌细胞系的协同凋亡。DR 5/Fc嵌合蛋白可明显阻断协同凋亡作用。芬维A胺和TRAIL协同激活caspase-3、-8、-10和-9以及Bid和PARP的切割，并且这种激活在DR 5/Fc嵌合蛋白存在下也被阻断。这些结果表明芬维A胺诱导的细胞凋亡被TRAIL敏化。因此，芬维A胺和TRAIL的联合治疗可能是一种有前途的治疗结直肠癌的模型。
Fenretinide (N-[4-Hydroxyphenyl]retinamide; 4HPR) is a semisynthetic retinoid that induces apoptosis in a variety of malignancies. Fenretinide has been examined in clinical trials as a cancer chemopreventive and chemotherapeutic agent. Oxidative stress induced by fenretinide has been shown to mediate apoptosis through a mitochondrial pathway by the induction of a transcription factor CCAAT/ enhancer binding protein homologous protein (CHOP) and Bak. In this study, we report that fenretinide induces death receptor 5 (DR5)/TRAIL-R2 up-regulation via the induction of the transcription factor CHOP in colon cancer cell lines. Fenretinide induced DR5 expression at protein and mRNA levels. Furthermore, fenretinide increased DR5 promoter activity and the enhanced activity decreased by mutation of the CHOP binding site. CHOP was also up-regulated by fenretinide at the promoter level. We also showed that combined treatment with fenretinide and TRAIL induced synergistic apoptosis in colon cancer cell lines. The synergistic apoptosis was markedly blocked by DR5/Fc chimeric protein. Fenretinide and TRAIL cooperatively activated caspase-3, -8, -10 and -9 and cleavage of Bid and PARP, and this activation was also blocked in the presence of DR5/Fc chimeric protein. These results indicate that fenretinide-induced apoptosis is sensitized by TRAIL. Therefore, combined treatment with fenretinide and TRAIL might be a promising model for the treatment of colorectal cancer.