Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O· production in cancer cells

Marco Cordani, Giovanna Butera, Ilaria Dando, Margalida Torrens-Mas, Elena Butturini, Raffaella Pacchiana, Elisa Oppici, Chiara Cavallini, Sara Gasperini, Nicola Tamassia, Mercedes Nadal-Serrano, Michela Coan, Davide Rossi, Gianluca Gaidano, Michele Caraglia, Sofia Mariotto, Riccardo Spizzo, Pilar Roca, Jordi Oliver, Maria Teresa ScupoliMassimo Donadelli

Research output: Contribution to journalArticle

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 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. 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.

Original languageEnglish
Pages (from-to)994-1008
Number of pages15
JournalBritish Journal of Cancer
Volume119
Issue number8
DOIs
Publication statusPublished - Oct 16 2018

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AMP-Activated Protein Kinases
p53 Genes
Reactive Oxygen Species
B-Cell Chronic Lymphocytic Leukemia
Neoplasms
Protein Isoforms
Prodrugs
Tumor Suppressor Genes
Immunoblotting
Drug Resistance
Sulfhydryl Compounds
Confocal Microscopy
Reverse Transcription
Transfection
Cysteine
Pancreas
Breast
Down-Regulation
Cell Proliferation
Uncoupling Protein 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cordani, M., Butera, G., Dando, I., Torrens-Mas, M., Butturini, E., Pacchiana, R., ... Donadelli, M. (2018). Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O· production in cancer cells. British Journal of Cancer, 119(8), 994-1008. https://doi.org/10.1038/s41416-018-0288-2

Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O· production in cancer cells. / Cordani, Marco; Butera, Giovanna; Dando, Ilaria; Torrens-Mas, Margalida; Butturini, Elena; Pacchiana, Raffaella; Oppici, Elisa; Cavallini, Chiara; Gasperini, Sara; Tamassia, Nicola; Nadal-Serrano, Mercedes; Coan, Michela; Rossi, Davide; Gaidano, Gianluca; Caraglia, Michele; Mariotto, Sofia; Spizzo, Riccardo; Roca, Pilar; Oliver, Jordi; Scupoli, Maria Teresa; Donadelli, Massimo.

In: British Journal of Cancer, Vol. 119, No. 8, 16.10.2018, p. 994-1008.

Research output: Contribution to journalArticle

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 & Donadelli, M 2018, 'Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O· production in cancer cells', British Journal of Cancer, vol. 119, no. 8, pp. 994-1008. https://doi.org/10.1038/s41416-018-0288-2
Cordani, Marco ; Butera, Giovanna ; Dando, Ilaria ; Torrens-Mas, Margalida ; Butturini, Elena ; Pacchiana, Raffaella ; Oppici, Elisa ; Cavallini, Chiara ; Gasperini, Sara ; Tamassia, Nicola ; Nadal-Serrano, Mercedes ; Coan, Michela ; Rossi, Davide ; Gaidano, Gianluca ; Caraglia, Michele ; Mariotto, Sofia ; Spizzo, Riccardo ; Roca, Pilar ; Oliver, Jordi ; Scupoli, Maria Teresa ; Donadelli, Massimo. / Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O· production in cancer cells. In: British Journal of Cancer. 2018 ; Vol. 119, No. 8. pp. 994-1008.
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T1 - Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O2ˉ· production in cancer cells

AU - Cordani, Marco

AU - Butera, Giovanna

AU - Dando, Ilaria

AU - Torrens-Mas, Margalida

AU - Butturini, Elena

AU - Pacchiana, Raffaella

AU - Oppici, Elisa

AU - Cavallini, Chiara

AU - Gasperini, Sara

AU - Tamassia, Nicola

AU - Nadal-Serrano, Mercedes

AU - Coan, Michela

AU - Rossi, Davide

AU - Gaidano, Gianluca

AU - Caraglia, Michele

AU - Mariotto, Sofia

AU - Spizzo, Riccardo

AU - Roca, Pilar

AU - Oliver, Jordi

AU - Scupoli, Maria Teresa

AU - Donadelli, Massimo

PY - 2018/10/16

Y1 - 2018/10/16

N2 - 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 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. 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.

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