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Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

S Shen1, O Kepp, M Michaud

  • 1INSERM, U848, Villejuif, France.

Oncogene
|May 18, 2011
PubMed

Insights

This study investigated if chemotherapy drugs kill cancer cells via autophagy. Researchers found no compounds that induce cell death through autophagy, suggesting it rarely causes cell death in human cells.

Area of Science:

  • Cell Biology
  • Oncology
  • Pharmacology

Background:

  • Autophagy is a cellular process involved in degradation and recycling.
  • The role of autophagy in cancer chemotherapy is not fully understood.
  • Chemotherapeutic agents can induce various cell death pathways, including apoptosis, necrosis, and autophagy.

Purpose of the Study:

  • To determine if established or experimental anticancer chemotherapeutics can induce cell death via autophagy.
  • To screen a large set of cytotoxic agents for their effects on autophagy, apoptosis, and necrosis.
  • To investigate the mechanism of cell death induced by compounds that stimulate autophagic flux.

Main Methods:

  • High-content screening of approximately 1400 cytotoxic agents.
  • Simultaneous assessment of autophagy, apoptosis, and necrosis parameters.
  • Systematic analysis of autophagic flux in potent GFP-LC3 puncta inducers.
  • ATG7 gene knockdown to assess the role of autophagy in cell death.

Main Results:

  • Many agents induced a 'pure' autophagic, apoptotic, or necrotic phenotype.
  • Fewer than 100 compounds simultaneously induced autophagy, apoptosis, and necrosis.
  • 59 out of 80 potent GFP-LC3 puncta inducers truly stimulated autophagic flux.
  • Microtubule inhibitors induced apoptosis or necrosis but not autophagic flux.
  • ATG7 knockdown did not attenuate cell death induced by agents causing GFP-LC3 puncta.

Conclusions:

  • No single compound was found to induce cell death by autophagy in this screening.
  • Autophagy is rarely, if ever, the executed mechanism of cell death in human cells.
  • Chemotherapeutic agents primarily induce cell death through apoptosis or necrosis, even when affecting autophagy markers.

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