Abstract
Purpose: The high incidence of biliary tract carcinoma in patients with anomalous pancreaticobiliary ductal junction (APBDJ) implicates that a compositional alteration in bile may contribute to the genesis of this cancer. Lysophosphatidylcholine (LPC) is generated in the bile of these patients. Given the role of cyclooxygenase-2 (COX-2) in biliary tract carcinogenesis, we postulated that LPC induces COX-2 in cholangiocytes. Methods: The effect of LPC on COX-2 expression in cholangiocytes was evaluated by immunoblot analysis, real-time PCR and reporter gene assay. Apoptosis was induced by TRAIL treatment, and quantified using DAPI staining. Results: Lysophosphatidylcholine increased COX-2 protein expression in cholangiocytes in a concentration- and time-dependent manner. LPC-induced Raf-1 activation was responsible for this COX-2 induction. Accordingly, LPC increased COX-2 mRNA levels in a Raf-1 dependent manner by stabilizing COX-2 mRNA. Finally, LPC attenuated TRAIL-mediated apoptosis through a COX-2/PgE2 dependent mechanism. Conclusions: Collectively, these results implicate that LPC inhibits cholangiocyte apoptosis by inducing COX-2 expression via a Raf-1 dependent mechanism. This anti-apoptotic signaling may participate in biliary tract carcinogenesis in APBDJ patients, and therefore, its interruption may be a viable chemopreventative strategy.
Original language | English (US) |
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Pages (from-to) | 771-779 |
Number of pages | 9 |
Journal | Journal of Cancer Research and Clinical Oncology |
Volume | 132 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2006 |
Keywords
- Anomalous pancreaticobiliary ductal junction
- Apoptosis
- Biliary tract carcinoma
- Cyclooxygenase-2
- Lysophosphatidylcholine
ASJC Scopus subject areas
- Oncology
- Cancer Research