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

Nat Commun. 2013;4:2130. doi: 10.1038/ncomms3130.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Antineoplastic Agents / pharmacology*
  • Aurora Kinase B / metabolism
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Autophagy-Related Protein 5
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cisplatin / pharmacology
  • DNA Damage / drug effects*
  • DNA Damage / genetics
  • Etoposide / pharmacology
  • HSP90 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • 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*
  • Mitosis / drug effects*
  • Mitosis / genetics
  • Neoplasms / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction / drug effects
  • Survivin

Substances

  • ATG5 protein, human
  • Antineoplastic Agents
  • Autophagy-Related Protein 5
  • BIRC5 protein, human
  • HSP90 Heat-Shock Proteins
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Survivin
  • Etoposide
  • AURKB protein, human
  • Aurora Kinase B
  • Cisplatin