title: FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria.
abstract: Several stimuli induce programmed cell death by increasing Ca(2+) transfer from the endoplasmic reticulum (ER) to mitochondria. Perturbation of this process has a special relevance in pathologies as cancer and neurodegenerative disorders. Mitochondrial Ca(2+) uptake mainly takes place in correspondence of mitochondria-associated ER membranes (MAM), specialized contact sites between the two organelles. Here, we show the important role of FATE1, a cancer-testis antigen, in the regulation of ER-mitochondria distance and Ca(2+) uptake by mitochondria. FATE1 is localized at the interface between ER and mitochondria, fractionating into MAM FATE1 expression in adrenocortical carcinoma (ACC) cells under the control of the transcription factor SF-1 decreases ER-mitochondria contact and mitochondrial Ca(2+) uptake, while its knockdown has an opposite effect. FATE1 also decreases sensitivity to mitochondrial Ca(2+)-dependent pro-apoptotic stimuli and to the chemotherapeutic drug mitotane. In patients with ACC, FATE1 expression in their tumor is inversely correlated with their overall survival. These results show that the ER-mitochondria uncoupling activity of FATE1 is harnessed by cancer cells to escape apoptotic death and resist the action of chemotherapeutic drugs.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire CNRS UMR 7275 Sophia Antipolis, Valbonne, France NEOGENEX CNRS International Associated Laboratory, Valbonne, France University of Nice - Sophia Antipolis, Valbonne, France.
authors.forename: Mabrouka
authors.initials: M
authors.lastname: Doghman-Bouguerra
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy CNR Neuroscience Institute, Padova, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Granatiero
authors.affiliation: Department of Internal Medicine I - Endocrine Unit, University Hospital University of Würzburg, Würzburg, Germany.
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.affiliation: Department of Internal Medicine I - Endocrine Unit, University Hospital University of Würzburg, Würzburg, Germany.
authors.forename: Iuliu
authors.initials: I
authors.lastname: Sbiera
authors.affiliation: University of Nice - Sophia Antipolis, Valbonne, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire CNRS UMR 7275 Sophia Antipolis, Valbonne, France University of Nice - Sophia Antipolis, Valbonne, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brau
authors.affiliation: Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy CNR Neuroscience Institute, Padova, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire CNRS UMR 7275 Sophia Antipolis, Valbonne, France NEOGENEX CNRS International Associated Laboratory, Valbonne, France University of Nice - Sophia Antipolis, Valbonne, France ninino@ipmc.cnrs.fr.
authors.forename: Enzo
authors.identifier: 0000-0002-0584-5681
authors.initials: E
authors.lastname: Lalli
mesh_terms: D018268:Adrenocortical Carcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D015870:Gene Expression; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism; D008939:Mitotane / Q000494:pharmacology; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D013256:Steroids / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; C449758:FATE1 protein, human; D013256:Steroids; D014157:Transcription Factors; D008939:Mitotane; D002118:Calcium
keywords: MAM; adrenal cortex; apoptosis; endocrine cancer; mitochondria