Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O2ˉ· production in cancer cells

• DOI: 10.1038/s41416-018-0288-2
• Publication Date: 2018-10-10T16:07:16Z
• Authors: Marco Cordani; Giovanna Butera; Ilaria Dando; Margalida Torrens...; Elena Butturini; Raffaella Pacchiana; Elisa Oppici; Chiara Cavallini; Sara Gasperini; Nicola Tamassia; Mercedes Nadal-Se...; Michela Coan; Davide Rossi; Gianluca Gaidano; Michele Caraglia; Sofia Mariotto; Riccardo Spizzo; Pilar Roca; Jordi Oliver; Maria Teresa Scupoli; Massimo Donadelli
• Keywords: Adult; Male; 0301 basic medicine; Cancer Research; 570; 616-006.04; 610; AMP-Activated Protein Kinases; Article; Oncología; 03 medical and health sciences; 3207 Patología; Cell Line, Tumor; Neoplasms; Humans; Uncoupling Protein 2; Oncogenes; Tumour-suppressor proteins;; Heat-Shock Proteins; Aged; Aged, 80 and over; Free Radical Scavengers; Middle Aged; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Acetylcysteine; Mitochondria; 3. Good health; Oxygen; Oncology; MCF-7 Cells; Female; Biología celular (Biología); Tumor Suppressor Protein p53; Reactive Oxygen Species

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 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.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.