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

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.

• Authors: Alicja Sznarkowska, Anna Kostecka, Anna Kawiak, Pilar Acedo, Mattia Lion, Alberto Inga, Joanna Zawacka-Pankau
• Journal: Cell division (Cell Div) Vol. 13 Pg. 10 ( 2018) ISSN: 1747-1028 [Print] England
• PMID: 30603043 (Publication Type: Journal Article)