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Changes in metabolism affect expression of ABC transporters through ERK5 and depending on p53 status

2017; Impact Journals LLC; Volume: 9; Issue: 1 Linguagem: Inglês

10.18632/oncotarget.23305

1949-2553

Sana Belkahla, Abrar Ul Haq Khan, Delphine Gitenay, Catherine Alexia, Claire Gondeau, Dang-Nghiem Vo, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Guillaume Cartron, Javier Hernández, Martine Daujat‐Chavanieu, Nerea Allende-Vega, Martín Villalba,

Peroxisome Proliferator-Activated Receptors

// Sana Belkahla 1 , Abrar Ul Haq Khan 1, 2 , Delphine Gitenay 1, 2 , Catherine Alexia 1, 2 , Claire Gondeau 1, 2, 3 , Dang-Nghiem Vo 1 , Stefania Orecchioni 4 , Giovanna Talarico 4 , Francesco Bertolini 4 , Guillaume Cartron 5 , Javier Hernandez 1 , Martine Daujat-Chavanieu 1, 2 , Nerea Allende-Vega 1, 2, * and Martin Villalba Gonzalez 1, 2, * 1 Department of Lymphocyte Differentiation, Tolerance and Metabolism: Basis for Immunotherapy, Institut De Médecine Régénératrice Et Biothérapie (IRMB), INSERM, Univ De Montpellier, Montpellier, France 2 Department of Lymphocyte Differentiation, Tolerance and Metabolism: Basis for Immunotherapy, Institut De Médecine Régénératrice Et Biothérapie (IRMB), CHU Montpellier, Montpellier, France 3 Département d'Hépato-gastroentérologie A, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France 4 Department of Oncology and Hemato-Oncology, European Institute of Oncology, Milan, Italy 5 Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier I, Montpellier, France * These two authors share senior authorship Correspondence to: Martin Villalba Gonzalez, email: martin.villalba@inserm.fr Nerea Allende-Vega, email: nerea.allende-vega@inserm.fr Keywords: ABC transporter; p53; ERK5; oxidative phosphorylation (OXPHOS); dichloroacetate (DCA) Received: June 10, 2017 Accepted: December 05, 2017 Published: December 14, 2017 ABSTRACT Changes in metabolism require the efflux and influx of a diverse variety of metabolites. The ABC superfamily of transporters regulates the exchange of hundreds of substrates through the impermeable cell membrane. We show here that a metabolic switch to oxidative phosphorylation (OXPHOS), either by treating cells with dichloroacetate (DCA) or by changing the available substrates, reduced expression of ABCB1, ABCC1, ABCC5 and ABCG2 in wild-type p53-expressing cells. This metabolic change reduced histone changes associated to active promoters. Notably, DCA also inhibited expression of these genes in two animal models in vivo . In contrast, OXPHOS increased the expression of the same transporters in mutated (mut) or null p53-expressing cells. ABC transporters control the export of drugs from cancer cells and render tumors resistant to chemotherapy, playing an important role in multiple drug resistance (MDR). Wtp53 cells forced to perform OXPHOS showed impaired drug clearance. In contrast mutp53 cells increased drug clearance when performing OXPHOS. ABC transporter promoters contain binding sites for the transcription factors MEF2, NRF1 and NRF2 that are targets of the MAPK ERK5. OXPHOS induced expression of the MAPK ERK5. Decreasing ERK5 levels in wtp53 cells increased ABC expression whereas it inhibited expression in mutp53 cells. Our results showed that the ERK5/MEF2 pathway controlled ABC expression depending on p53 status.