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Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling

Emma Sandilands1, Bryan Serrels, David G McEwan

  • 1Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, UK.

Nature Cell Biology
|December 6, 2011
PubMed

Insights

Cancer cells survive pathway disruption by sequestering active Src via autophagy. Inhibiting this process restores Src to adhesions, leading to cancer cell death, revealing a new therapeutic target.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • The Src/FAK pathway is crucial for cancer cell survival and migration.
  • Perturbations in this pathway can trigger cell death.
  • Cancer cells develop mechanisms to evade apoptosis under stress.

Purpose of the Study:

  • To elucidate the mechanism by which cancer cells survive Src/FAK pathway disruption.
  • To identify potential therapeutic vulnerabilities associated with this survival mechanism.
  • To investigate the role of autophagy in regulating Src activity during pathway perturbation.

Main Methods:

  • Depletion of Focal Adhesion Kinase (FAK) and Src.
  • Expression of non-phosphorylatable FAK proteins.
  • Cell detachment assays.
  • Immunofluorescence microscopy to observe Src localization.
  • Autophagy inhibition studies.
  • Co-immunoprecipitation to identify protein complexes.

Main Results:

  • Cancer cells sequester active Src into intracellular puncta upon Src/FAK pathway perturbation.
  • These puncta co-localize with autophagy regulators, indicating autophagic involvement.
  • Inhibition of autophagy restores active Src to focal adhesions, inducing cancer cell death.
  • Autophagic targeting of active Src involves a Src-LC3B complex mediated by c-Cbl via its LC3-interacting region, independent of its E3 ligase activity.

Conclusions:

  • c-Cbl-mediated autophagic targeting of active Src is a survival mechanism in cancer cells when the integrin/Src/FAK pathway is disrupted.
  • This process represents a novel cancer cell vulnerability.
  • Targeting this autophagic pathway offers a potential new therapeutic strategy for cancer treatment.

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