title: c-Src dependency of NSAID-induced effects on NF-κB-mediated apoptosis in colorectal cancer cells.
abstract: 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.
authors.affiliation: Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. richardbrady@btinternet.com
authors.forename: Richard R W
authors.initials: RR
authors.lastname: Brady
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Loveridge
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Stark
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D019061:src-Family Kinases; D001241:Aspirin