ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy

Anticancer drug therapy activates both molecular cell death and autophagy pathways. Here we show that even sublethal concentrations of DNA-damaging drugs, such as etoposide and cisplatin, induce the expression of autophagy-related protein 5 (ATG5), which is both necessary and sufficient for the subs...

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Veröffentlicht in:	Nature communications Jg. 4; H. 1; S. 2130 - 14
Hauptverfasser:	Maskey, Dipak, Yousefi, Shida, Schmid, Inès, Zlobec, Inti, Perren, Aurel, Friis, Robert, Simon, Hans-Uwe
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 2013 Nature Publishing Group Nature Pub. Group Nature Portfolio
Schlagworte:	631/337/1427 631/67/1059 631/80/641/1655 631/80/82/39 Active Transport, Cell Nucleus Antineoplastic Agents - pharmacology Antineoplastic drugs Aurora Kinase B - metabolism Autophagy Autophagy - drug effects Autophagy - genetics Autophagy-Related Protein 5 Caspase Cell death Cell Line, Tumor Cell Nucleus - metabolism Chemotherapy Chromosomes Cisplatin Cisplatin - pharmacology Cytosol Damage Deoxyribonucleic acid DNA DNA damage DNA Damage - drug effects DNA Damage - genetics Drug therapy Etoposide Etoposide - pharmacology HeLa Cells HSP90 Heat-Shock Proteins - metabolism Humanities and Social Sciences Humans Inhibitor of Apoptosis Proteins - metabolism Jurkat Cells M Phase Cell Cycle Checkpoints - drug effects M Phase Cell Cycle Checkpoints - genetics Microtubule-Associated Proteins - biosynthesis Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Misalignment Mitosis Mitosis - drug effects Mitosis - genetics multidisciplinary Neoplasms - metabolism Nuclei (cytology) Phagosomes Proteins Radiation therapy RNA Interference RNA, Small Interfering Science Science (multidisciplinary) Signal transduction Signal Transduction - drug effects Survivin
ISSN:	2041-1723, 2041-1723
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Zusammenfassung:	Anticancer drug therapy activates both molecular cell death and autophagy pathways. Here we show that even sublethal concentrations of DNA-damaging drugs, such as etoposide and cisplatin, induce the expression of autophagy-related protein 5 (ATG5), which is both necessary and sufficient for the subsequent induction of mitotic catastrophe. We demonstrate that ATG5 translocates to the nucleus, where it physically interacts with survivin in response to DNA-damaging agents both in vitro and in carcinoma tissues obtained from patients who had undergone radiotherapy and/or chemotherapy. As a consequence, elements of the chromosomal passenger complex are displaced during mitosis, resulting in chromosome misalignment and segregation defects. Pharmacological inhibition of autophagy does not prevent ATG5-dependent mitotic catastrophe, but shifts the balance to an early caspase-dependent cell death. Our data suggest a dual role for ATG5 in response to drug-induced DNA damage, where it acts in two signalling pathways in two distinct cellular compartments, the cytosol and the nucleus. The protein ATG5 is known to be involved in the formation of autophagosomes. Here, Maskey et al . identify a new role of ATG5 in response to drug-induced DNA damage whereby ATG5 translocates to the nucleus, leading to chromosome misalignment and mitotic catastrophe.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms3130