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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O2-· production in cancer cells
Marco Cordani1,2, Giovanna Butera1, Ilaria Dando1
1Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy.
Background:
The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy.
Methods:
A 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.
Results:
We 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 O2-· 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.
Conclusions:
The 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.
Insights
Mutant p53 actively promotes cancer by inhibiting SESN1 expression, disrupting the AMPK/PGC-1α/UCP2 pathway. Restoring UCP2 or using antioxidants reverses these oncogenic effects, suggesting pro-oxidant drugs for TP53-mutant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The TP53 tumor suppressor gene is frequently altered in various cancers.
- Mutant p53 gain-of-function isoforms are known to promote cancer malignancy.
Purpose of the Study:
- To investigate the molecular mechanisms by which mutant p53 promotes cancer.
- To identify potential therapeutic targets for TP53-mutant cancers.
Main Methods:
- Utilized a panel of wild-type and mutant p53 cancer cell lines from diverse tissues (pancreas, breast, skin, lung) and chronic lymphocytic leukemia (CLL) patients.
- Assessed the effects of mutant p53 using confocal microscopy, reactive oxygen species assays, immunoblotting, and quantitative RT-PCR after cellular transfection.
Main Results:
- Oncogenic mutant p53 isoforms inhibit SESN1 expression, downregulating the AMPK/PGC-1α/UCP2 axis and reducing mitochondrial O2-· production.
- A correlation was observed between decreased reduced thiols and poorer clinical outcomes in CLL patients with mutant TP53.
- Restoration of UCP2 expression or addition of N-acetyl-L-cysteine reversed mutant p53's oncogenic effects, including hyper-proliferation, anti-apoptosis, and drug resistance.
Conclusions:
- Inhibition of the SESN1/AMPK/PGC-1α/UCP2 axis by mutant p53 contributes to its pro-oxidant and oncogenic effects.
- Pro-oxidant drugs represent a potential therapeutic strategy for cancer patients with mutant TP53.
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