Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

Abstract

The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.

Oncogenic pathways activated by pro-inflammatory cytokines promote mutant p53 stability: clue for novel anticancer therapies

“…Interestingly, mTOR may be also activated by cytokines [74,75] and, as UPR has a key role in regulating the release of these molecules, UPR signaling could contribute to mTOR activation also by increasing the production of these cytokines. Of note, mutp53, in contrast to its wild-type counterpart, may support mTOR signaling, sustaining an oxidative environment that leads to uncontrolled cancer cell proliferation [76]. Indeed, it has been recently reported that hotspot mutp53 promotes the phosphorylation of the mTORC1 targets S6K1 and 4EBP1 in both colon and non-small carcinoma cells [77].…”

Ellagic Acid-Derived Urolithins as Modulators of Oxidative Stress

“…However, mutant p53-driven ROS accumulation was also shown to enhance cell sensitivity to H 2 O 2 treatment. It was then speculated that mutant p53-bearing cancer cells could be significantly more sensitive to prooxidant drugs [82]. In conclusion, the final effect of p53 activation seems to be dependent on the cell type, p53 isoform, level of p53 activity, and its location within the cell and can promote cell proliferation, migration, further genotoxic damage, senescence, or cell death.…”

Ligation-Mediated Polymerase Chain Reaction Detection of 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine and 5-Hydroxycytosine at the Codon 176 of the p53 Gene of Hepatitis C-Associated Hepatocellular Carcinoma Patients

“…Through increasing the expression of antioxidant genes, such as glutathione peroxidase and aldehyde dehydrogenase 4, p53 can prevent excessive ROS production that could compromise genome integrity [32,33]. In contrast with the wild-type, mutant p53 proteins sustain ROS formation and promote tumor progression by regulating Nrf2 and PGC-1α target genes [34].…”