ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis

Cell Death Differ. 2014 Apr;21(4):612-23. doi: 10.1038/cdd.2013.186. Epub 2014 Jan 10.

Abstract

Rescue of the p53 tumor suppressor is an attractive cancer therapy approach. However, pharmacologically activated p53 can induce diverse responses ranging from cell death to growth arrest and DNA repair, which limits the efficient application of p53-reactivating drugs in clinic. Elucidation of the molecular mechanisms defining the biological outcome upon p53 activation remains a grand challenge in the p53 field. Here, we report that concurrent pharmacological activation of p53 and inhibition of thioredoxin reductase followed by generation of reactive oxygen species (ROS), result in the synthetic lethality in cancer cells. ROS promote the activation of c-Jun N-terminal kinase (JNK) and DNA damage response, which establishes a positive feedback loop with p53. This converts the p53-induced growth arrest/senescence to apoptosis. We identified several survival oncogenes inhibited by p53 in JNK-dependent manner, including Mcl1, PI3K, eIF4E, as well as p53 inhibitors Wip1 and MdmX. Further, we show that Wip1 is one of the crucial executors downstream of JNK whose ablation confers the enhanced and sustained p53 transcriptional response contributing to cell death. Our study provides novel insights for manipulating p53 response in a controlled way. Further, our results may enable new pharmacological strategy to exploit abnormally high ROS level, often linked with higher aggressiveness in cancer, to selectively kill cancer cells upon pharmacological reactivation of p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases
  • DNA Damage / drug effects
  • DNA Repair
  • HCT116 Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MCF-7 Cells
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oxidants / pharmacology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Protein Phosphatase 2C
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / analysis
  • Reactive Oxygen Species / metabolism
  • Thioredoxin Reductase 1 / metabolism
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cell Cycle Proteins
  • MCL1 protein, human
  • MDM4 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nuclear Proteins
  • Oxidants
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • Hydrogen Peroxide
  • TXNRD1 protein, human
  • Thioredoxin Reductase 1
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • PIK3CB protein, human
  • JNK Mitogen-Activated Protein Kinases
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C