Abstract:
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.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Cordani M,Butera G,Dando I,Torrens-Mas M,Butturini E,Pacchiana R,Oppici E,Cavallini C,Gasperini S,Tamassia N,Nadal-Serrano M,Coan M,Rossi D,Gaidano G,Caraglia M,Mariotto S,Spizzo R,Roca P,Oliver J,Scupoli MT,Donaddoi
10.1038/s41416-018-0288-2subject
Has Abstractpub_date
2018-10-01 00:00:00pages
994-1008issue
8eissn
0007-0920issn
1532-1827pii
10.1038/s41416-018-0288-2journal_volume
119pub_type
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