Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53

Cancer Res. 2015 Sep 15;75(18):3842-52. doi: 10.1158/0008-5472.CAN-13-1079. Epub 2015 Aug 20.

Abstract

The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Colorectal Neoplasms / pathology
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Gene Knockdown Techniques
  • Genes, p53
  • Humans
  • Irinotecan
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Nitrofurans / chemistry
  • Nitrofurans / pharmacology*
  • Nitrofurans / toxicity
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Piperazines / toxicity
  • Proteolysis
  • Proto-Oncogene Mas
  • RNA, Small Interfering / pharmacology
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / drug effects*
  • Tumor Protein p73
  • Tumor Stem Cell Assay
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*
  • Xenograft Model Antitumor Assays

Substances

  • 1-(4-methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • MAS1 protein, human
  • Neoplasm Proteins
  • Nitrofurans
  • Nuclear Proteins
  • Piperazines
  • Proto-Oncogene Mas
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • TP53 protein, human
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Irinotecan
  • Camptothecin