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Live Cell Imaging of Early Autophagy Events: Omegasomes and Beyond
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Live Cell Imaging of Early Autophagy Events: Omegasomes and Beyond

Published on: July 27, 2013

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Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition

Christina G Towers1, Brent E Fitzwalter1, Daniel Regan2

  • 1Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Developmental Cell
|August 6, 2019
PubMed

Insights

Cancer cells can overcome autophagy inhibition by upregulating NRF2, but this adaptation makes them vulnerable to proteasome inhibitors, offering new therapeutic strategies.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • Autophagy is crucial for cancer cell survival, yet mechanisms of resistance to its inhibition remain unclear.
  • Understanding how cancer cells adapt to autophagy loss is vital for developing effective cancer therapies.

Purpose of the Study:

  • To investigate how cancer cells circumvent autophagy inhibition.
  • To identify molecular mechanisms driving resistance to autophagy loss in cancer.
  • To explore potential therapeutic vulnerabilities arising from this adaptation.

Main Methods:

  • Development of a CRISPR/Cas9 assay with dynamic live-cell imaging.
  • Measurement of acute gene knockout effects on cancer cell growth and protein homeostasis.
  • Analysis of NRF2 pathway involvement in circumventing autophagy inhibition.

Main Results:

  • Some cancer cells depend on autophagy for growth as much as DNA replication.
  • Highly autophagy-dependent cancer cells upregulate NRF2 to survive autophagy gene knockout (KO).
  • NRF2 upregulation is sufficient for cells to maintain protein homeostasis despite ATG7 KO.
  • This adaptation confers increased susceptibility to proteasome inhibitors.

Conclusions:

  • A common mechanism of acquired resistance to autophagy inhibition involves NRF2 upregulation.
  • Cancer cells adapting to avoid autophagy dependency develop new, actionable vulnerabilities.
  • Targeting proteasome pathways may be effective against cancer cells resistant to autophagy inhibition.
Keywords:
ATG7CRISPR/Cas9NRF2autophagycancerchloroquine resistanceoxidative stressproteasomal degradation

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