Activation of FXR or TGR inhibits inflammatory response via

Activation of FXR or TGR5 inhibits inflammatory response via repressing NF-κB activity [1]. FXR is not expressed or expressed at a very low level in macrophages [45] (data not shown), but highly expressed in hepatocytes. In contrast, TGR5 is expressed in macrophages but not in hepatocytes. Our data suggest that both FXR and TGR5 play a role in INT-767-mediated inhibition of hepatic inflammatory cytokines, consistent with the anti-inflammatory function of both FXR and TGR5.
Introduction The nuclear receptor Farnesoid X Receptor (FXR) has historically been considered primarily as a regulator of metabolism and has multifaceted functions in maintaining the homeostasis of bile acid, lipid and glucose levels in the liver [1], [2], [3]. Recent studies suggest that FXR is also a tumor suppressor in liver tissue [4], [5], [6]. FXR plays an important role in inhibiting liver carcinogenesis and progression. FXR exerts an anti-carcinogenic effect in liver tissue through diverse mechanisms [7]. Limitless replicative potential is one of the hallmarks of cancer cells, which, in human tumors, is caused by deregulated growth signaling pathways [8]. Both exogenous FXR and FXR agonists repress the proliferation of liver cancer cells in vitro and the growth of cancerous xenografts in nude mice in vivo [6], [7], [8], [9]. This suggests that FXR may play a role in suppressing deregulated signaling pathways in cancerous cells. The mammalian Target of Rapamycin (mTOR) is a well-conserved serine/threonine kinase that participates in the signaling network that regulates cell growth and metabolism [10]. mTOR interacts with many proteins and it is part of two distinct multi-protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [11]. While the functions of mTORC2 remain mysterious, mTORC1 has a well-documented sensitivity to rapamycin, and it plays a central role in the promotion of cell proliferation by integrating inputs from five major signals—amino HMP Linker abundance, energy status, growth factors, hypoxia, and genotoxic stress [11], [12]. The direct role of mTOR-dependent mechanisms in the proliferation and survival of many kinds of cancer cells is well documented [12], [13], [14]. Activated mTORC1 induces phosphorylation of its target kinase S6K which then drives accumulation of many oncogenic products [12]. Our previous studies indicated that FXR inhibited the growth of human hepatocellular carcinoma (HCC) cells both in vitro and in vivo [6]. To further explore the possible mechanisms by which FXR exerts this function, we used lentiviral induction of FXR overexpression in liver cancer cells, and then determined differentially expressed genes by mRNA microarray. Analysis of these data suggested that FXR is involved in regulating the mTOR/S6K signaling pathway. We then performed further investigations into the FXR-mediated suppression of mTOR/S6K signaling.
Materials and methods
Results
Discussion As an endogenous bile acid sensor, FXR is indispensable in maintaining liver metabolism homeostasis and is regarded as a liver protector. An increasing body of evidence from cell and animal experiments and clinical studies indicate that FXR is an inhibitor of tumors in liver tissue [7]. However, the details of the regulatory mechanism by which FXR controls liver tumor cell behavior remain largely unresolved. Our previous study showed that FXR inhibited the growth of HCC cells both in vitro and in vivo [6]. The data presented here further confirmed this observation. In addition, we found FXR induced cell-cycle arrest when we analyzed the liver cancer cells with different expression level of FXR. Involvement of mTOR-dependent signaling pathways in both metabolic diseases and cancers has been previously reported. Activation of mTORC1 favors tumorigenesis by promoting transcription of oncogenes, enhancing angiogenesis, inhibiting autophagy, and enhancing lipid accumulation [12]. Deregulation of major components of the mTOR pathway has significant effects in many types of cancer, including liver cancer [15]. Several studies indicate that mTOR activation is involved in the initiation of liver cancer and plays a role in the malignant transition of hepatocytes to HCC [10], [12]. Constitutive activation of the mTOR pathway in HCC is correlated with multiple malignant clinicopathological features regardless of etiology [15]. As an important target of mTORC1, the major roles of S6K is in control of translation and cell growth [16].