The role of bile acids in cellular invasiveness of gastric cancer

Abstract

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Bile acids have been implicated in the development of digestive tract malignancy such as colonic, gastric and esophageal neoplasms by epidemiological, clinical and animal studies. Several studies have shown that the growth and transformation signaling by most of the bile acids is through the activation of protein kinase C (PKC) and induction of cyclooxygenase-2 (COX-2) gene expression. The highly hydrophobic bile acids such as chenodeoxycholic acid (CD) and deoxycholic acid can promote carcinogenesis and stimulate the invasion of colon cancer cells. On the contrary, ursodeoxycholic acid (UDCA), a less hydrophobic stereoisomer of CD, inhibits proliferation and induces apoptosis in colon cancer cells. We have examined the effects of bile acid on human gastric cancer cells MKN-74. Exposure of CD led to activation of PKC alpha, increased COX-2 gene expression and increased prostaglandin E2 (PGE2) synthesis. The induced COX-2 protein expression could be detected within 4-h exposure of 200 μM CD, and it was dose- and time-dependent. PGE2 is the product of COX-2, and has been reported to cause tumor invasion and angiogenesis in animal study. Safingol, a PKC inhibitor, and thalidomide could suppress CD-induced COX-2 protein expression and PGE2 production. UDCA suppressed CD-induced PGE2 production but not COX-2 protein expression. Using a Boyden chamber invasion assay, both safingol and UDCA could impede CD-induced tumor invasiveness by 30-50%. Our results indicate that signaling of hydrophobic bile acid such as CD in gastric cancer is probably through PKC activation and COX-2 induction, which may give rise to anti-apoptosis, invasion and angiogenesis. By perturbing the bile acid pool, UDCA can attenuate CD-induced PGE2 synthesis and tumor invasiveness. UDCA holds a great potential as anti-cancer and chemopreventive agent in gastric cancer. (Supported by China Medical University Hospital DMR-91-032 and Taiwan National Science Council 91-2314-B-039-006.)