Abstract
BackgroundBile acids have been implicated in the development of digestive tract malignancy by epidemiological, clinical and animal studies. The growth and transformation signaling by most of the bile acids is thought to be related to the induced cyclooxygenase-2 (COX-2) expression and increased production of prostaglandin E2 (PGE2). 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 examined the effects of bile acid on human gastric cancer cells MKN-74.MethodsEarly-passage human gastric cancer MKN-74 cells were used for drug treatment, preparation of whole cell lysates, subcellular extracts and Western blot analysis. The levels of PGE2 released by the cells were measured by enzyme inummoassay to indicate COX-2 enzymatic activity. Cellular invasion assay was performed in Boyden chamber.ResultsExposure of CD led to activation of protein kinase C (PKC) alpha, increased COX-2 expression and increased 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 (SAF), a PKC inhibitor, suppressed the COX-2 protein expression and PGE2 production by CD in MKN-74. Furthermore, UDCA suppressed PGE2 production by CD but did not affect COX-2 protein expression induced by CD. Using a Boyden chamber invasion assay, both SAF and UDCA impeded CD induced tumor invasiveness of MKN-74 by 30–50%.ConclusionsOur results indicate that signaling of hydrophobic bile acid such as CD in gastric cancer cells is through PKC activation and COX-2 induction, which leads to increased cellular invasion. By perturbing the bile acid pool, UDCA attenuates CD-induced PGE2 synthesis and tumor invasiveness.
Highlights
Bile acids have been implicated in the development of digestive tract malignancy by epidemiological, clinical and animal studies
Our results indicate that signaling of hydrophobic bile acid such as chenodeoxycholic acid (CD) in gastric cancer cells is through protein kinase C (PKC) activation and COX-2 induction, which leads to increased cellular invasion
We examined the effect of PKC inhibitor SAF on CD-induced PKCα activation and COX-2 protein expression
Summary
Bile acids have been implicated in the development of digestive tract malignancy by epidemiological, clinical and animal studies. Ursodeoxycholic acid (UDCA), a less hydrophobic stereoi‐ somer of CD, inhibits proliferation and induces apoptosis in colon cancer cells. Wu et al Cancer Cell Int (2018) 18:75 bile acids with increased hydrophobicity such as CD and DCA have a greater capacity to pass through cell membrane and modulate signaling cascades for tumorigenesis in normal colonic cells [7, 8]. UDCA inhibits proliferation and induces apoptosis in colon cancer cells [10,11,12]. UDCA inhibits proliferation and induce apoptosis in colon cancer cells [18, 19]. We have examined the effects of bile acid on human gastric cancer cells MKN-74
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