PT  - JOURNAL ARTICLE
AU  - Alicja Sznarkowska
AU  - Anna Kostecka
AU  - Anna Kawiak
AU  - Pilar Acedo
AU  - Mattia Lion
AU  - Alberto Inga
AU  - Joanna Zawacka-Pankau
TI  - Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in <em>TP</em>53-deficient cancer cells
AID  - 10.1101/357293
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 357293
4099  - http://biorxiv.org/content/early/2018/08/15/357293.short
4100  - http://biorxiv.org/content/early/2018/08/15/357293.full
AB  - 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 (ALA) 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.Conclusion Our findings may in future contribute to the successful repurposing of PpIX into clinical practice.TAtranscriptionally activePpIXprotoporphyrin IXCDDPcisplatinCXHcycloheximide