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Role of Src signal transduction pathways in scatter factor-mediated cellular protection

Saijun Fan1, Qinghui Meng, John J Laterra

  • 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.

The Journal of Biological Chemistry
|December 3, 2008
PubMed

Insights

Scatter factor (SF) and its receptor c-Met activate Src signaling pathways, enhancing NF-kappaB activity and promoting chemoresistance against adriamycin (ADR). These novel pathways involve Src, Rac1, MKK3/6, p38, TAK1, and NF-kappaB-inducing kinase.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Scatter factor (SF), also known as hepatocyte growth factor, is implicated in tumor invasion, angiogenesis, and chemoresistance.
  • SF/c-Met signaling pathways are crucial for cellular survival and resistance to DNA-damaging agents like adriamycin (ADR).
  • Previous research identified a phosphatidylinositol 3-kinase/c-Akt/Pak1/NF-kappaB survival pathway in SF-mediated chemoresistance.

Purpose of the Study:

  • To elucidate the mechanisms by which SF and its receptor c-Met confer chemoresistance against adriamycin (ADR).
  • To investigate the role of Src signaling pathways in SF-mediated cell protection and NF-kappaB activation.
  • To delineate novel signaling cascades involved in SF/c-Met-driven resistance to DNA-damaging chemotherapy.

Main Methods:

  • Investigated the involvement of Src signaling in SF-mediated protection against adriamycin (ADR) using cancer cell models.
  • Assessed the impact of Src kinase and Src homology 3 domains on NF-kappaB activity and ADR resistance.
  • Utilized Western blotting and kinase assays to analyze the activation of key signaling molecules including Akt, IkappaB kinase, Rac1, MKK3/6, p38, TAK1, and NF-kappaB-inducing kinase.

Main Results:

  • Endogenous Src is essential for SF-stimulated NF-kappaB activity and cell protection against ADR.
  • Src enhances SF-induced NF-kappaB activation by stimulating Akt and IkappaB kinase activity.
  • SF activates Src and downstream pathways including Rac1/MKK3/6/p38 and Src/TAK1/NF-kappaB-inducing kinase, contributing to ADR resistance.

Conclusions:

  • Src signaling pathways play a critical role in SF/c-Met-mediated chemoresistance.
  • Novel cross-talk between Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-kappaB-inducing kinase pathways contributes to SF-driven NF-kappaB activation.
  • These findings provide new insights into the molecular mechanisms underlying chemoresistance in SF/c-Met-overexpressing tumors.

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