Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1
Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1
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DOI：
10.1158/1535-7163.mct-06-0521
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发表时间：
2007-04-01
影响因子：
5.7
通讯作者：
Bonavida, Benjamin
中科院分区：
文献类型：
--
作者：
Baritaki, Stavroula;Huerta-Yepez, Sara;Bonavida, Benjamin
几种化疗药物与肿瘤坏死因子相关凋亡诱导配体（TRAIL）组合通过上调DR 5表达导致对TRAIL介导的凋亡的抗性逆转。DR 5的启动子有一个推测的结合位点，可与Yang 1（YY 1）中的转录抑制子结合，因此，我们推测致敏药物可能抑制YY 1。我们发现用各种化疗药物治疗肿瘤细胞可抑制核因子-κ B。我们研究了药物是否也抑制YY 1活性，以及YY 1抑制是否与DR 5表达的上调和细胞对TRAIL诱导的凋亡的敏感性相关。用CDDP、VP-16、ADR和长春新碱处理TRAIL和耐药前列腺癌PC-3细胞系。DR 5荧光素酶报告构建体和针对YY 1的小干扰RNA用于确定YY 1在DR 5转录中的作用。用各种化疗药物预处理PC-3细胞和其他肿瘤细胞系使细胞对TRAIL诱导的凋亡敏感，同时上调DR 5表达和抑制YY 1表达及其DNA结合活性。用野生型DR 5报告基因转染的PC-3细胞中的基线荧光素酶活性在用YY 1结合位点携带缺失或突变的DR 5构建体转染的细胞中显著增强。用药物处理增强了DR 5野生型荧光素酶活性，而用YY 1缺失或YY 1突变的构建体转染的细胞没有增加。YY 1小干扰RNA转染的细胞显示DR 5表达上调，并对TRAIL介导的凋亡敏感。这些发现提供了证据表明，药物诱导的肿瘤细胞对TRAIL的敏感性部分是通过抑制转录抑制因子YY 1和上调DR 5表达来介导的。因此，YY 1可能是逆转对TRAIL诱导的细胞凋亡的抗性的潜在治疗靶点。
Several chemotherapeutic drugs in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) result in reversal of resistance to TRAIL-mediated apoptosis through up-regulation of DR5 expression. The promoter of DR5 has one putative binding site for the transcription repressor in Yang 1 (YY1), and thus, we hypothesized that the sensitizing drugs may inhibit YY1. We have found that treatment of tumor cells with various chemotherapeutic drugs inhibited nuclear factor-kappa B. We examined whether drugs also inhibit YY1 activity and whether YY1 inhibition correlates with up-regulation of DR5 expression and sensitization of cells to TRAIL-induced apoptosis. The TRAIL- and drug-resistant prostate carcinoma PC-3 cell line was treated with CDDP, VP-16, ADR, and vincristine. DR5 luciferase reporter constructs and small interfering RNA against YY1 were used to determine the role of YY1 in DR5 transcription. Pretreatment of PC-3 cells and other tumor cell lines with various chemotherapeutic drugs sensitized the cells to TRAIL-induced apoptosis concurrently with up-regulation of DR5 expression and inhibition of YY1 expression and its DNA-binding activity. The baseline luciferase activity in PC-3 cells transfected with the wildtype DR5 reporter was significantly augmented in cells transfected with DR5 constructs carrying deletions or mutation in the YY1-binding site. Treatment with drug enhanced DR5 wild-type luciferase activity, with no increase in cells transfected with the YY1-deleted or YY1-mutated constructs. Cells transfected with YY1 small interfering RNA showed up-regulation of DR5 expression and sensitization to TRAIL-mediated apoptosis. The findings provide evidence that drug-induced sensitization of tumor cells to TRAIL is mediated, in part, by inhibition of the transcription repressor YY1 and up-regulation of DR5 expression. Hence, YY1 may be a potential therapeutic target to reverse resistance to TRAIL-induced apoptosis.