p53 as a hub in cellular redox regulation and therapeutic target in cancer

Abstract

The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription is tightly regulated by post-translational modifications and is dependent on a reducing cellular environment. Some p53 transcriptional target genes are involved in regulation of the cellular redox homeostasis, e.g. TIGAR and GLS2. A large fraction of human tumors carry TP53 mutations, most commonly missense mutations that lead to single amino acid substitutions in the core domain. Mutant p53 proteins can acquire so called gain-of-function activities and influence the cellular redox balance in various ways, for instance by binding of the Nrf2 transcription factor, a major regulator of cellular redox state. The DNA-binding core domain of p53 has 10 cysteine residues, three of which participate in holding a zinc atom that is critical for p53 structure and function. Several novel compounds that refold and reactivate missense mutant p53 bind to specific p53 cysteine residues. These compounds can also react with other thiols and target components of the cellular redox system, such as glutathione. Dual targeting of mutant p53 and redox homeostasis may allow more efficient treatment of cancer.

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

“…The earliest MDM2 antagonist, nutlin (Hoffman-La Roche), rationally-designed cis-imidazoline compound, binds to the hydrophobic cleft of the MDM2 and mimicks p53 residues in the MDM2 binding motif; Phe 19 , Trp 23 , and Leu 2611 . Idasanutlin (RG73388), the most advanced derivative of nutlin, has shown a promising result in Phase I trial in patients with acute myeloid leukemia (AML) 12 and has advanced to Phase III trial for relapsed/refractory AML (https://clinicaltrials.gov/show/NCT02545283).…”

“…This restores wt-p53 function and induces cancer cells death 18 . Besides p53, MQ reacts with and inhibits thioredoxin reductase, which induces ROS in cancer cells 19 . It was tested in TP53-mutated myelodysplastic syndromes in combination with azacitidine (https://clinicaltrials.gov/show/NCT03745716).…”

Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells

“…DNA damage, and induces cell cycle arrest, apoptosis and/or senescence 9 . p53 can also regulate redox homeostasis 10 and energy metabolism 11 . Activation of p53 by cellular stress leads to transcriptional transactivation of p53 target genes such as p21 that blocks cell cycle progression, and Bax, Puma, and Noxa that promote apoptosis 12 .…”

The iron–sulphur cluster in human DNA2 is required for all biochemical activities of DNA2

“…A few decades ago, the tumour suppressor p53 37 , and more recently, the transcription factor Brf2 38 and the homologous recombination protein RAD51 39 , were found to contain oxygenreactive cysteines. In the case of the transcription factor Brf2, its redox-reactive cysteine was found to interact with the TATA box, and DNA binding was reversibly impaired upon oxidation of the protein 38 .…”