Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O· production in cancer cells
Cordani, Marco (Universidad Autónoma de Madrid. Instituto de Investigaciones Biomédicas "Alberto Sols")
Butera, Giovanna (University of Verona. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry)
Dando, Ilaria (University of Verona. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry)
Torrens-Mas, Margalida (Institut d'Investigació Sanitària de Palma)
Butturini, Elena (University of Verona. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry)
Pacchiana, Raffaella (University of Verona. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry)
Oppici, Elisa (University of Verona. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry)
Cavallini, Chiara (University of Verona. Research Center LURM (Interdepartmental Laboratory of Medical Research))
Gasperini, Sara (Section of General Pathology, University of Verona. Department of Medicine)
Tamassia, Nicola (Section of General Pathology, University of Verona. Department of Medicine)
Nadal-Serrano, Mercedes (Vall d'Hebron Institut d'Oncologia)
Coan, Michela (National Cancer Institute (Aviano, Itàlia))
Rossi, Davide (Institute of Oncology Research)
Gaidano, Gianluca (University of Eastern Piedmont. Division of Hematology, Department of Translational Medicine)
Caraglia, Michele (Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy)
Mariotto, Sofia (University of Verona. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry)
Spizzo, Riccardo (National Cancer Institute (Aviano, Itàlia))
Roca, Pilar (Institut d'Investigació Sanitària de Palma)
Oliver, Jordi (Institut d'Investigació Sanitària de Palma)
Scupoli, Maria Teresa (University of Verona. Research Center LURM (Interdepartmental Laboratory of Medical Research))
Donadelli, Massimo (University of Verona. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry)
Universitat Autònoma de Barcelona

Date:	2018
Abstract:	The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy. 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. 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 Oˉ· 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--cysteine, reversed the oncogenic effects of mutant p53 as cellular hyper-proliferation, antiapoptotic effect, and resistance to drugs. 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Oncogenes ; Tumour-suppressor proteins
Published in:	British Journal of Cancer, Vol. 119 (october 2018) , p. 994-1008, ISSN 1532-1827

DOI: 10.1038/s41416-018-0288-2
PMID: 30318520

15 p, 1.5 MB

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