Transcription Factors Sp1 and p73 Control the Expression of the Proapoptotic Protein NOXA in the Response of Testicular Embryonal Carcinoma Cells to Cisplatin
Transcription Factors Sp1 and p73 Control the Expression of the Proapoptotic Protein NOXA in the Response of Testicular Embryonal Carcinoma Cells to Cisplatin
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DOI：
10.1074/jbc.m112.376319
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发表时间：
2012-08-03
影响因子：
4.8
通讯作者：
Fernandez-Luna, Jose L.
中科院分区：
文献类型：
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作者：
Grande, Lara;Bretones, Gabriel;Fernandez-Luna, Jose L.
睾丸生殖细胞肿瘤（TGCTs）对顺铂为基础的化疗具有高度反应性，即使在晚期也可治愈。我们研究了顺铂诱导细胞凋亡的分子机制，发现顺铂暴露后，即使在没有p53的情况下，NTERA 2顺铂敏感细胞中的促凋亡Noxa转录上调，但在1411 HP耐药细胞中不上调。阻断Noxa可降低胚胎癌（EC）NTERA 2细胞对顺铂的凋亡反应。对Noxa启动子的详细分析表明，p73和Sp1样因子Sp1和KLF6在该基因的转录控制中起关键作用。TAp73的过表达诱导Noxa，而显性阴性同种型Delta Np73在NTERA 2和2102EP中顺铂暴露后降低Noxa水平。有趣的是，Sp1的下调增加了Noxa对顺铂的反应。然而，KLF6的阻断降低了顺铂诱导的EC细胞系中Noxa的上调。此外，TGCT的组织微阵列分析显示，Noxa的表达与胚胎癌患者的良好临床预后相关。因此，我们的数据显示了调控EC细胞中Noxa的转录网络，这是其对顺铂化疗的凋亡反应的关键，并提出Noxa作为治疗反应的预测因子。
Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform Delta Np73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response.