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Cell Div. 2018 Dec 26;13:10. doi: 10.1186/s13008-018-0043-3. eCollection 2018.

Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells.

Author information

1
1Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.
2
2Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Biomedicum, Solnavägen 9, 171 65 Stockholm, Sweden.
3
3Centre for Integrative Biology, CIBIO, University of Trento, via Sommarive 9, 38123 Trento, Italy.
4
4Present Address: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.

Abstract

Background:

The p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and p53 and thus, acts as an oncogene.

Results:

By employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch. Finally, PpIX showed potent antitumor effect and inhibited the growth of xenograft human tumors in mice.

Conclusion:

Our findings may in future contribute to the successful repurposing of PpIX into clinical practice.

KEYWORDS:

Apoptosis; Itch; MDM2; MDMX; Protoporphyrin IX; TAp73; Yeast-based assay

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