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

Abstract

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. 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.

Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy inTP53 mutant pancreatic tumors

“…It has been demonstrated that PpIX reactivates TAp73 tumor suppressor and induces TAp73-dependent apoptosis in TP 53-null cancer cells[17]. To assess if the growth inhibition observed in PDAC cell lines by PpIX and BPD is a result of apoptosis, we evaluated the expression of TAp73 and its pro-apoptotic targets in two pancreatic cancer cells lines.…”

“…We have shown in a drug-repurposing approach that PpIX re-activates wild-type p53 and TAp73 and induces apoptosis in cancer cells. The mechanism is via inhibition of p53/MDM2 and TAp73/MDM2(X) interactions[16, 17]. Next, PpIX was identified in the in vitro screening as a potent, competitive inhibitor of thioredoxin reductase (TrxR)[25].…”

“…Protoporphyrin IX, itself, without light excitation, was shown to induce wild-type p53-related cell death in several human cancer cell lines including human colon carcinoma[16]. Next, it has recently been demonstrated that PpIX stabilizes and activates TAp73 and induces TAp73-dependent apoptosis in cancer cells lacking TP 53[17].…”

The p53/MDM2/MDMX-targeted therapies—a clinical synopsis

“…p53 acts together with p73 and p63 proteins in tumor suppression 4 . In addition to p53, exo-PpIX activates p73 by binding to N-terminal domain and inhibits the p73/ MDM2 and p73/MDMX interactions 16 . In our recent work in Cell Death Discovery, we confirmed that both p53 and p73 were activated by exo-PpIX in B-CLL cells.…”

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

“…Next, it was shown that PpIX stabilizes TAp73 protein levels in p53-null cancer cells, induces TAp73-dependent transcription and activates apoptotic NOXA and PUMA. Also, PpIX ablated MDM2/MDMX/p73/ITCH complex and inhibited tumor growth of p53-null subcutaneous xenografts via activation of TAp73 and Poly (ADP-ribose) polymerase (PARP) cleavage [144] (Figure 4).…”