c-Src dependency of NSAID-induced effects on NF-κB-mediated apoptosis in colorectal cancer cells

Carcinogenesis. 2011 Jul;32(7):1069-77. doi: 10.1093/carcin/bgr077. Epub 2011 May 5.


Long-term aspirin or related non-steroidal anti-inflammatory drugs (NSAIDs) ingestion can protect against colorectal cancer (CRC). NSAIDs have a pro-apoptotic activity and we have shown that stimulation of the nuclear factor-kappaB (NF-κB) pathway is a key component of this pro-apoptotic effect. However, the upstream pathways have yet to be fully elucidated. Here, we demonstrate that aspirin activates the c-Src tyrosine kinase pathway in CRC cells. We show that c-Src activation occurs in a time- and dose-dependent manner, preceding aspirin-mediated degradation of IκBα, nuclear/nucleolar translocation of NF-κB/RelA and induction of apoptosis. Furthermore, inhibition of c-Src activity, by chemical inhibition or expression of a kinase dead form of the protein abrogates aspirin-mediated degradation of IκBα, nuclear translocation of RelA and apoptosis, suggesting a causal link. Expression of constitutively active c-Src mimics aspirin-induced stimulation of the NF-κB pathway. The NSAIDs sulindac, sulindac sulphone and indomethacin all similarly activate a c-Src-dependent NF-κB and apoptotic response. These data provide compelling evidence that c-Src is an upstream mediator of aspirin/NSAID effects on NF-κB signalling and apoptosis in CRC cells and have relevance to the development of future chemotherapeutic/chemopreventative agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Apoptosis / drug effects*
  • Aspirin / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Colorectal Neoplasms / pathology*
  • Humans
  • Immunohistochemistry
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Signal Transduction / drug effects
  • src-Family Kinases / metabolism
  • src-Family Kinases / physiology*


  • Anti-Inflammatory Agents, Non-Steroidal
  • NF-kappa B
  • src-Family Kinases
  • Aspirin