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

• Published in: Cell death and differentiation Vol. 21; no. 4; pp. 612 - 623
• Main Authors: Shi, Y, Nikulenkov, F, Zawacka-Pankau, J, Li, H, Gabdoulline, R, Xu, J, Eriksson, S, Hedström, E, Issaeva, N, Kel, A, Arnér, E S J, Selivanova, G
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2014
• Subjects: Apoptosis; Apoptosis - drug effects; Biochemistry; Biology; Breast cancer; Cancer therapies; Cell cycle; Cell death; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; DNA damage; DNA Damage - drug effects; DNA Repair; Gene expression; HCT116 Cells; Humans; Hydrogen Peroxide - pharmacology; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; MCF-7 Cells; Medicin och hälsovetenskap; Metabolism; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original Paper; 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; Reactive Oxygen Species - analysis; Reactive Oxygen Species - metabolism; RNA, Small Interfering - metabolism; Senescence; Signal transduction; Thioredoxin Reductase 1 - metabolism; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Sweden
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/cdd.2013.186

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.