Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Abstract

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.

The Dark Side of E2F1: In Transit beyond Apoptosis

“…The consequences of mutant p53 accumulation include increased chemoresistance and enhanced ability to metastasize (30). In this context, it seems interesting that E2F1 binds the TP53 promoter and is necessary for efficient induction of mutant p53 upon drug treatment in vitro (29). The findings are in line with a cell contextdependent synergism between E2F1 and DNA-damaging agents in the upregulation of genes that are related to cell survival and tumor progression (3,31).…”

“…Because EZH2 is induced by E2F1 as well as genotoxic stress, it is reasonable, if not logical, to assume that anticancer drugs can even potentiate apoptosis evasion and cancer metastasis. This assumption also becomes apparent from a recent article by Bug and Dobbelstein (29). The tumor suppressor p53 is mutated in about half of all human malignancies and accumulates to levels that by far exceed those of wild-type p53.…”

Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group

“…Some studies have shown that mutations in L2 and L3 domains, which are critical regions responsible for DNA binding, were associated with poor prognosis in breast cancer and correlated with resistance to doxorubicin [26, 35]. In turn, Bug et al [36] have shown that even closely related anthracyclines induce the synthesis of different, opposing transcripts from p53 locus. Therefore, the minor differences in treatment schedule can influence the results concerning p53 prognostic role.…”

Overlapping Region of p53/Wrap53 Transcripts: Mutational Analysis and Sequence Similarity with microRNA-4732-5p

“…Recently several lines of evidences have shown that wrap53 is upregulated by some therapeutic agents such as idarubicin, etoposid and cisplatein (Bug and Dobbelstein, 2011;Yuan et al, 2011). Also it is going to be a new biomarker for cancer diagnosis (Zhang et al, 2012).…”