Department of Molecular Oncology, Göttingen Center of Molecular Biosciences-GZMB, Ernst Caspari Haus, University of Göttingen, Göttingen, Germany.
Oncogene. 2011 Aug 18;30(33):3612-24. doi: 10.1038/onc.2011.72. Epub 2011 Mar 28.
Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its gain of function. Its accumulation is partially due to enhanced stability, but little is known about how the mRNA levels of mutant p53 can be regulated. Likewise, the impact of cancer therapy on the levels of mutant p53 is poorly understood. We show here that the anthracyclines doxorubicin, daunorubicin and epirubicin further increase the amounts of mutant p53 mRNA and protein in cancer cells. Moreover, we show for the first time that the transcription factor E2F1 associates with the promoter DNA of TP53. Upon genotoxic treatment, E2F1 contributed to the expression of mutant p53, both directly and through induction of TAp73. In contrast, the anthracycline idarubicin and also another topoisomerase inhibitor, etoposide, failed to increase the levels of p53 mRNA, despite their ability to induce the synthesis of TAp73 mRNA. Instead, a natural antisense transcript of TP53, WRAP53, was strongly augmented by idarubicin and etoposide, but only less so by the other anthracyclines under study. RNA corresponding to the first exon of WRAP53 was mainly found in cell nuclei and it reduced the levels of mutant p53. Taken together, this suggests a reciprocal activation pattern of TP53 and WRAP53 by different chemotherapeutics. Reducing the levels of mutant p53 by small-interfering RNA increased chemosensitivity, and idarubicin prevented cell survival more efficiently than the mutant p53-inducing doxorubicin. We conclude that even closely related anthracyclines induce the synthesis of different, opposing transcripts from the TP53 locus. When using these drugs for cancer therapy, the increased levels of mutant p53 may augment its gain of function and thus favor unwanted chemoresistance and tumor progression.
突变型 p53 经常在癌细胞中积累，并促进肿瘤细胞侵袭，这是其获得功能的一部分。其积累部分是由于稳定性增强，但对于突变型 p53 的 mRNA 水平如何受到调节知之甚少。同样，癌症治疗对突变型 p53 水平的影响也了解甚少。我们在这里表明，蒽环类药物阿霉素、柔红霉素和表柔比星进一步增加了癌细胞中突变型 p53 mRNA 和蛋白的含量。此外，我们首次表明转录因子 E2F1 与 TP53 的启动子 DNA 结合。在遗传毒性处理后，E2F1 通过直接诱导 TAp73 和间接诱导 TAp73 促进突变型 p53 的表达。相比之下，蒽环类药物伊达比星和另一种拓扑异构酶抑制剂依托泊苷尽管能够诱导 TAp73 mRNA 的合成，但未能增加 p53 mRNA 的水平。相反，TP53 的一种天然反义转录物 WRAP53 被伊达比星和依托泊苷强烈增强，但在研究中的其他蒽环类药物中则较少。WRAP53 的第一个外显子对应的 RNA 主要存在于细胞核中，它降低了突变型 p53 的水平。总的来说，这表明不同的化疗药物对 TP53 和 WRAP53 有相互激活的模式。通过小干扰 RNA 降低突变型 p53 的水平会增加化疗敏感性，而伊达比星比诱导突变型 p53 的阿霉素更有效地阻止细胞存活。我们得出结论，即使是密切相关的蒽环类药物也会诱导来自 TP53 基因座的不同、相反的转录本的合成。当使用这些药物进行癌症治疗时，突变型 p53 水平的增加可能会增强其获得的功能，从而导致不必要的化疗耐药性和肿瘤进展。
