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TP53 is the most frequently mutated tumor suppressor gene in human cancer (Kandoth et al. 2013).
TP53 mutations cause the expression of full length p53 proteins that are characterized not only by a
loss of function but which also exert additional oncogenic features (Oren & Rotter 2010). They are
caused in part by the inhibitory interaction of MUTp53 with the tumor suppressor TAp73 (Como et al.
1999). In accordance with established data, here it was demonstrated that mutated p53 proteins inhibit
the transcriptional potential of WTp53 and TAp73. The small molecule RETRA disrupts the MUTp53-
TAp73 interaction and thereby reactivates transcriptional functions of TAp73 (Kravchenko et al.
2008). In agreement, the transcriptional potential of TAp73 inhibited by mutated structurally stable
and unstable p53 proteins was restored by RETRA. Moreover, RETRA increased the transcriptional
potential of TAp73 itself. Whether this was the result of a specific RETRA-mediated effect on the
structure of the TAp73 C-terminus or transcription inhibitory domain remains to be elucidated.
During treatment of a heterogenous panel of tumor cell lines with RETRA varying cytotoxic effects
were observed. Retrospectively, analyses of the treated cell lines revealed that the cytotoxicity caused
by RETRA was independent of the p53 mutational status and structural features of p53 that influence
the MUTp53/TAp73 interaction. There was no correlation with the mRNA expression of TAp73 and
dNp73 in the treated cell lines. Yet, this has to be appraised with caution since the treated cell line
panel was highly heterogeneous and quantifying the expression of the p73 isoforms at the mRNA level
is of limited predictive value in respect to their functional status. The combined treatment of tumor cell
lines with RETRA and etoposide, an inhibitor of topoisomerase II, caused additive cytotoxic effects
independent of their p53 mutational status. In addition, in MUTp53-expressing or p53 negative cell
lines synergistic effects of RETRA and etoposide were observed. Retrospectively, the lack of a
cytotoxic stimulus might have caused a random error during the conducted correlation analysis.
The presented data confirm the hypothesis that RETRA can reactivate the transcriptional and tumor
suppressive activity of TAp73. Additional research in vitro and in vivo is needed to confirm RETRA’s
suspected mechanism of action. This could put forward the idea of combining chemosensitizing
features of RETRA with conventional chemotherapeutics in the treatment of malignant tumors. This
would also provide a possibility to reduce established doses of chemotherapeutics to minimize side
effects or to intensify cancer treatment. Additionally, because TAp73 is only rarely mutated in human
cancer RETRA may contribute to overcome radio- and chemoresistance mediated by p53 mutations.