Prodigiosin rescues deficient p53 signaling and antitumor effects via upregulating p73 and disrupting its interaction with mutant p53.

Abstract

p53 reactivation offers a broad-based strategy for cancer therapy. In this study, we report the identification of prodigiosin that can reactivate p53 family-dependent transcriptional activity in p53-deficient human colon cancer cells. Prodigiosin and its structural analogue (compound R) induced the expression of p53 target genes accompanied by cell-cycle arrest and apoptosis in p53-deficient cancer cells. Prodigiosin restored p53 signaling in cancer cells harboring hotspot TP53 mutations, with little to no detectable cytotoxicity in normal human fibroblasts and with no genotoxicity. Prodigiosin induced the expression of p73 and disrupted its interaction with mutant p53, thereby rescuing p53 pathway deficiency and promoting antitumor effects. The disruption of mutant p53/p73 interaction was specific to prodigiosin and not related to mTOR inhibition. Our findings suggest that mutant p53 needs to be targeted in the context of p73 stimulation to allow efficient restoration of the p53 pathway. In exhibiting this capability, prodigiosin and its analogue provide lead compounds to rescue deficiencies in the p53 pathway in cancer cells by upregulating p73 and targeting mutant p53/p73 interaction there.

• Authors: Bo Hong, Varun V Prabhu, Shengliang Zhang, A Pieter J van den Heuvel, David T Dicker, Levy Kopelovich, Wafik S El-Deiry
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 4 Pg. 1153-65 (Feb 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24247721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• DNA-Binding Proteins
• Mutant Proteins
• Nuclear Proteins
• TP73 protein, human
• Trp73 protein, mouse
• Tumor Protein p73
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Prodigiosin

Topics

• Animals
• DNA-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, Tumor Suppressor (drug effects)
• Genes, p53 (drug effects)
• HCT116 Cells
• Humans
• Mice
• Mice, Nude
• Mutant Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Prodigiosin (pharmacology)
• Protein Binding (drug effects)
• Signal Transduction (drug effects, genetics)
• Tumor Cells, Cultured
• Tumor Protein p73
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Up-Regulation (drug effects, genetics)
• Xenograft Model Antitumor Assays