Bile acids (BAs) are cholesterol derivatives synthesized in the liver and then secreted into the intestine for lipid absorption. There are numerous scientific reports describing BAs, especially secondary BAs, as strong carcinogens or promoters of colon cancers. Firstly, BAs act as strong stimulators of colorectal cancer (CRC) initiation by damaging colonic epithelial cells, and inducing reactive oxygen species production, genomic destabilization, apoptosis resistance, and cancer stem cells-like formation. Consequently, BAs promote CRC progression via multiple mechanisms, including inhibiting apoptosis, enhancing cancer cell proliferation, invasion, and angiogenesis. There are diverse signals involved in the carcinogenesis mechanism of BAs, with a major role of epidermal growth factor receptor, and its down-stream signaling, involving mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and nuclear factor kappa-light-chain-enhancer of activated B cells. BAs regulate numerous genes including the human leukocyte antigen class I gene, p53, matrix metalloprotease, urokinase plasminogen activator receptor, Cyclin D1, cyclooxygenase-2, interleukin-8, and miRNAs of CRC cells, leading to CRC promotion. These evidence suggests that targeting BAs is an efficacious strategies for CRC prevention and treatment.

The secondary bile acid lithocholic acid (LCA), an established tumor promoter, has been implicated in colorectal cancer (CRC) metastasis. Overexpression of interleukin-8 (IL-8) has been detected in CRC, and it contributes to poor prognosis. However, the effect of LCA on IL-8 expression is still undefined. In this study, we observed that LCA treatment induced IL-8 expression in CRC HCT116 cells. Pharmacological inhibition and mutagenesis studies indicated that Erk1/2 is critical for LCA-induced IL-8 expression. Furthermore, LCA reduced the phosphorylation of STAT3, and the STAT3 inhibitor Stattic, accelerated LCA-induced IL-8 expression, suggesting that STAT3 is involved in LCA-induced IL-8 expression. Activation of Erk1/2 functioned as an upstream signal of the STAT3 suppression induced by LCA. In conclusion, LCA activated Erk1/2 and in turn, suppressed STAT3 phosphorylation to induce IL-8 expression in HCT116 cells, thus stimulating endothelial cell proliferation and tube like formation. J. Cell. Biochem. 118: 2958-2967, 2017. © 2017 Wiley Periodicals, Inc.

Metformin, an inexpensive, well-tolerated oral agent that is a commonly used first-line treatment for type 2 diabetes, has become the focus of intense research as a potential anticancer agent. In this study, we describe the inhibitory effect of metformin in interleukin 8 (IL-8) upregulation by lithocholic acid (LCA) in HCT116 colorectal cancer (CRC) cells. Pharmacological inhibition studies indicated that reactive oxygen species (ROS) were involved in LCA-induced IL-8 upregulation through activation of the transcription factor NF-κB. Metformin was demonstrated to block LCA-stimulated ROS production, in turn suppressing NF-κB signaling that was critical for IL-8 upregulation. An NADPH oxidase assay proved that the inhibitory effect of metformin on ROS production was derived from its strong suppression of NADPH oxidase, a key producer of ROS in cells. Compared with conditioned media (CM) derived from HCT116 cells treated with LCA, CM derived from HCT116 cells pretreated with metformin and then treated with LCA lost all stimulatory effect on endothelial cell proliferation and tubelike formation. In conclusion, metformin inhibited NADPH oxidase, which in turn suppressed ROS production and NF-κB activation to prevent IL-8 upregulation stimulated by LCA; this prevention thus obstructed endothelial cell proliferation and tubelike formation.

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