Abstract
BackgroundThe TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy.MethodsA panel of wild-type and mutant p53 cancer cell lines of different tissues, including pancreas, breast, skin, and lung were used, as well as chronic lymphocytic leukemia (CLL) patients with different TP53 gene status. The effects of mutant p53 were evaluated by confocal microscopy, reactive oxygen species production assay, immunoblotting, and quantitative reverse transcription polymerase chain reaction after cellular transfection.ResultsWe demonstrate that oncogenic mutant p53 isoforms are able to inhibit SESN1 expression and consequently the amount of SESN1/AMPK complex, resulting in the downregulation of the AMPK/PGC-1α/UCP2 axis and mitochondrial O2ˉ· production. We also show a correlation between the decrease of reduced thiols with a poorer clinical outcome of CLL patients bearing mutant TP53 gene. The restoration of the mitochondrial uncoupling protein 2 (UCP2) expression, as well as the addition of the radical scavenger N-acetyl-l-cysteine, reversed the oncogenic effects of mutant p53 as cellular hyper-proliferation, antiapoptotic effect, and resistance to drugs.ConclusionsThe inhibition of the SESN1/AMPK/PGC-1α/UCP2 axis contributes to the pro-oxidant and oncogenic effects of mutant p53, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing mutant TP53 gene.
Highlights
The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy
Mutant p53 increases mitochondrial reactive oxygen species (ROS) production To study the functional role of GOF mutant p53 proteins in the regulation of ROS production, we first analyzed the endogenous level of ROS by staining diverse cancer cell lines with the DCF probe
Mutant p53-dependent downregulation of the PGC-1α/uncoupling protein 2 (UCP2) axis is mediated by the blockage of SESN1/AMPK signaling As AMPK signaling pathway has a crucial role in many biological functions, including the induction of PGC-1α, we examined whether mutant p53 might inhibit PGC-1α/UCP2 axis through the upstream blockage of AMPK
Summary
The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy. In addition to the loss of the tumor suppression function of wild-type p53, GOF mutant p53 proteins contribute to the maintenance and stimulation of cancer growth through the acquisition of oncogenic functions.[2,3] In many tumors, p53 mutations are associated with high genomic instability, poor prognosis, reduced response to chemotherapy, promotion of migration, invasion and metastasis, and accelerated tumor recurrence.[4,5,6] Different models have been proposed to explain the GOF activities of mutant p53, including binding and inactivation of the p53 family members p63 and p73, modulation of the activity of a number of transcription factors, or the inactivation of DNA damage molecular sensors.[7,8,9] Our group documented that DNA damaging in cancer cells by gemcitabine drug stabilized the nuclear localization of mutant p53 proteins, which in turn triggered the expression of cell cycle-related genes, resulting in hyper-proliferation effects and chemoresistance.[10] In addition, we and others demonstrated that GOF mutant p53 isoforms can alter cancer cell metabolism,[11,12,13,14] autophagy response to various stimuli[15,16] and cancer microenvironment.[17,18] This broad spectrum of molecular properties indicates that GOF mutant p53 is involved in a plethora of different cellular pathways focused on cancer progression and aggressiveness
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