Abstract
Matrix metalloproteinase-9 (MMP-9) plays a crucial role in cell invasion and cancer metastasis. In this study, we showed that cholic acid (CA), a major primary bile acid, can induce MMP-9 expression in colon cancer HT29 and SW620 cells. CA increased reactive oxygen species (ROS) production and also activated phosphorylation of ERK1/2, JNK, and p38 MAPK. Specific inhibitors and mutagenesis studies showed that ERK1/2 and JNK functioned as upstream signals in the activation of AP-1, and p38 MAPK functioned as an upstream signal in the activation of NF-κB. N-acetyl-L-cysteine (NAC, an ROS scavenger) and diphenyleneiodonium chloride (DPI, an NADPH oxidase inhibitor) inhibited CA-induced activation of ERK1/2, JNK, and p38 MAPK, indicating that ROS production by NADPH oxidase could be the furthest upstream signal in MMP-9 expression. Colon cancer cells pretreated with CA showed remarkably enhanced invasiveness. Such enhancement was partially abrogated by MMP-9-neutralizing antibodies. These results demonstrate that CA could induce MMP-9 expression via ROS-dependent ERK1/2, JNK-activated AP-1, and p38-MAPK-activated NF-κB signaling pathways, which in turn stimulate cell invasion in human colon cancer cells.
Highlights
Colon cancer is the third most common human disease worldwide
To investigate the effect of bile acids on Matrix metalloproteinase-9 (MMP-9) expression, human colon SW620 and HT29 cells were treated with 30 μM of cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), and lithocholic acid (LCA) for 4 h and the level of matrix metalloproteinases (MMPs)-9 expression was determined by RT-PCR
CA and SW620 cells, which most significantly increased MMP-9 among the bile acids and cells used in Figure 1A,B, were employed in the following experiments
Summary
Colon cancer is the third most common human disease worldwide. The rate of relative survival following diagnosis is 65% at 5 years and 58% at 10 years [1]. As the end product of cholesterol catabolism, accounts for a major fraction of daily cholesterol turnover in humans It plays an important role in the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins in the intestine [3]. CA, a major primary bile acid, plays an important role in the digestion and absorption of dietary lipids and in cell invasion, growth, and apoptosis through various signaling pathways [6,7,8,9]. Cell invasion is a fundamental process for cancer metastasis It requires increased expression of proteases such as uroplaminogen-type activator (uPA) and matrix metalloproteinases (MMPs) [17]. We demonstrated that CA, a major primary bile acid, can induce cell invasion through MMP-9 expression in human colon cells. We elucidated the underlying molecular mechanism involved in such induction
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