AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells
| Autor: | Jörg Fahrer, Teresa Frisan, Bernd Kaina, Mahmoud Toulany, Carina Neitzel, Marc Audebert, Nina Seiwert, Svenja Stroh |
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| Přispěvatelé: | Department of Toxicology, University of Cagliari, Department of Cell and Molecular Biology, Karolinska Institutet [Stockholm], ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Department of Radiation Oncology, Division of Radiobiology and Molecular Environmental Research, University of Tuebingen, German Cancer Consortium, Johannes Gutenberg - Universität Mainz (JGU), Justus-Liebig-Universität Gießen (JLU), Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden, Partenaires INRAE, Métabolisme et Xénobiotiques (ToxAlim-MeX), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Fahrer, Jörg |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death autophagy appareil intestinal DNA damage [SDV]Life Sciences [q-bio] Immunology ATG5 Bacterial Toxins Ataxia Telangiectasia Mutated Proteins autophagie Biology Transfection human health akt2 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Downregulation and upregulation cellule intestinale Cell Line Tumor Humans DNA Breaks Double-Stranded Protein kinase B ComputingMilieux_MISCELLANEOUS différenciation cellulaire Autophagy Cell Biology santé humaine HCT116 Cells 3. Good health Cell biology 030104 developmental biology Apoptosis cancer colorectal 030220 oncology & carcinogenesis Gene Knockdown Techniques Cancer research [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology Original Article Signal transduction Tumor Suppressor Protein p53 Colorectal Neoplasms colorectal neoplasm Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cell Death and Disease Cell Death and Disease, Nature Publishing Group, 2017, 8 (8), 14 p. ⟨10.1038/cddis.2017.418⟩ Naunyn Schmiedeberg's Archives of Pharmacology 84. Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) 84. Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT), 2018, Gottingen, Germany. pp.1 HAL BASE-Bielefeld Academic Search Engine Cell Death & Disease Cell Death and Disease 8 (8), 14 p.. (2017) |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/cddis.2017.418⟩ |
| Popis: | DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells. We show that treatment of cells with CDT or IR increased the levels of the autophagy marker LC3B-II. Consistently, an enhanced formation of autophagosomes and a decrease of the autophagy substrate p62 were observed. Both CDT and IR concomitantly suppressed mTOR signaling and stimulated the autophagic flux. DSBs were demonstrated as the primary trigger of autophagy using a DNase I-defective CDT mutant, which neither induced DSBs nor autophagy. Genetic abrogation of p53 and inhibition of ATM signaling impaired the autophagic flux as revealed by LC3B-II accumulation and reduced formation of autophagic vesicles. Blocking of DSB-induced apoptotic cell death by the pan-caspase inhibitor Z-VAD stimulated autophagy. In line with this, pharmacological inhibition of autophagy increased cell death, while ATG5 knockdown did not affect cell death after DSB induction. Interestingly, both IR and CDT caused AKT activation, which repressed DSB-triggered autophagy independent of the cellular DNA-PK status. Further knockdown and pharmacological inhibitor experiments provided evidence that the negative autophagy regulation was largely attributable to AKT2. Finally, we show that upregulation of CDT-induced autophagy upon AKT inhibition resulted in lower apoptosis and increased cell viability. Collectively, the findings demonstrate that DSBs trigger pro-survival autophagy in an ATM- and p53-dependent manner, which is curtailed by AKT2 signaling. |
| Databáze: | OpenAIRE |
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