FXR blocks the growth of liver cancer cells through inhibiting mTOR-s6K pathway

Huang, Xiongfei; Zeng, Yeting; Wang, Xinrui; Ma, Xiaoxiao; Li, Qianqian; Li, Ningbo; Su, Hongying; Huang, Wendong

doi:10.1016/j.bbrc.2016.04.106

Cited by 20 publications

(18 citation statements)

References 17 publications

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“…In our study, ileal FXR expression is significantly lower after RYGB. Since FXR inhibits mTOR-S6K signaling pathway in liver cancer cells [ 46 ], reduction of ileal FXR may contribute to the hyperactivation of mTORC1 signaling after RYGB operation.…”

Section: Discussionmentioning

confidence: 99%

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Zhai

Peng

et al. 2018

EBioMedicine

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BackgroundThe mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings.MethodsCirculating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB.ResultsPositive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells.InterpretationDeoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB.

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Section: Discussionmentioning

confidence: 99%

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Zhai

Peng

et al. 2018

EBioMedicine

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“…However, there were various reports that FXR was elevated in multiple human cancers responsible for their initiation and progression [28, 29]. For instance, it is stated that FXR could suppress the proliferation of liver cancer via the inhibition of mTOR/S6K signaling [8]. On the other hand, some of the reports proposed the opposite; they showed that that the inhibition of FXR limits esophageal cancer growth [10].…”

Section: Discussionmentioning

confidence: 99%

“…Farnesoid X receptor (FXR) was a key receptor of BAs, and it was overexpression in various human malignancies associating with anti- and/or pro-tumoral roles. For instance, prior studies indicated that inactivation of FXR in cancer of liver and breast corresponded with increased propagation and decreased apoptosis [8, 9]. While, a study by B Guan and colleagues showed the opposite, they found that FXR inhibition limits the growth of esophageal cancer [10].…”

Section: Introductionmentioning

confidence: 99%

Correlated high expression of FXR and Sp1 in cancer cells confers a poor prognosis for pancreatic cancer: A study based on TCGA and tissue microarray

Han

et al. 2017

Oncotarget

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Bile acids (BAs) was critical in the initiation and progression of various tumors. However, their prognostic significance in pancreatic cancer was still illusive. In the present study, the expression and biological significance of FXR, a major receptor of BAs, in the lethal disease were evaluated in mRNA and protein levels. We found that FXR protein was elevated in the cancerous tissues, which was significantly higher than the adjacent tissues (p < 0.05). Meanwhile, our data showed that FXR was positively correlated with primary tumor location (p = 0.04) and poor survival (p = 0.002). Finally, COX regression model indicated that FXR protein was an independent prognostic factor (p = 0.01; HR = 2.15; 95% CI 1.27-3.63). Consistently, we also found a significant difference of FXR expression between the high and low groups in mRNA level (p < 0.001), and that high FXR expression confers a poor prognosis (p < 0.001). More importantly, the correlation assay showed that FXR was positively correlated Sp1 in both protein (r = 0.351, p = 0.008) and mRNA levels (r = 0.263, p < 0.01), with the simultaneously high expression indicated the worst prognosis on protein (p < 0.001) and mRNA levels (p < 0.001). Additionally, we also showed that FXR was elevated in the pancreatic cancer cells responsible for proliferation and migration. Overall, the data suggested co-high expression of the two factors was an independent prognostic factor (p < 0.001; HR = 3.27; 95% CI 1.86–5.76). Based on these data, we proposed a model to link FXR to Sp1, which included triggered FXR, p38/MAPK and/or PI3K/AKT signaling and phosphorylated Sp1, to illustrate the potential crosstalk between the two factors.

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“…It has been well documented that FXR also suppresses liver carcinogenesis and progression (5)(6)(7)(8). FXR may serve an indispensable role in inhibiting the activity of signaling pathways that are dysregulated in liver cancer cells (9).…”

Section: Introductionmentioning

confidence: 99%

“…It has been previously reported that FXR downregulation was correlated with the presence of multiple malignant clinicopathological features, including tumor size, advanced BCLC stage, poor differentiation and absence of encapsulation, in patients with HCC (7). FXR inhibited liver cancer cell proliferation in vivo and in vitro via inactivation of the mammalian target of rapamycin (mTOR)/ribosomal S6 kinase (S6K) pathway (9). The current study aimed to investigate whether FXR influenced the regulation liver cancer metastasis and the possible underlying mechanism.…”

Section: Introductionmentioning

confidence: 99%

Nuclear receptor FXR impairs SK‑Hep‑1 cell migration and invasion by inhibiting the Wnt/β‑catenin signaling pathway

Zeng

Wang

et al. 2020

Oncol Lett

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Recently, the nuclear receptor farnesoid X receptor (FXR) has been considered to be a liver tumor suppressor. However, the role of FXR in liver cancer invasion and metastasis remains unclear. The results of the current study demonstrated that FXR suppressed the migratory and invasive capacities of SK-Hep-1 cells in vitro and that FXR overexpression inhibited local invasion and lung metastasis of SK-Hep-1 xenografts in vivo. Bioinformatics analysis of the gene expression profile of SK-Hep-1 cells with different FXR levels indicated that FXR may regulate the Wnt/β-catenin pathway. Compared with controls, FXR-overexpressing SK-Hep-1 cells exhibited decreased expression of β-catenin target genes and reduced nuclear translocation of β-catenin proteins in vitro and in vivo. In conclusion, these results indicated that FXR may suppress SK-Hep-1 cell invasion and metastasis by suppressing the Wnt/β-catenin signaling pathway. The current study provided novel insight into the diagnosis and treatment of liver cancer.

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FXR blocks the growth of liver cancer cells through inhibiting mTOR-s6K pathway

Cited by 20 publications

References 17 publications

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Correlated high expression of FXR and Sp1 in cancer cells confers a poor prognosis for pancreatic cancer: A study based on TCGA and tissue microarray

Nuclear receptor FXR impairs SK‑Hep‑1 cell migration and invasion by inhibiting the Wnt/β‑catenin signaling pathway

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FXR blocks the growth of liver cancer cells through inhibiting mTOR-s6K pathway

Cited by 20 publications

References 17 publications

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Correlated high expression of FXR and Sp1 in cancer cells confers a poor prognosis for pancreatic cancer: A study based on TCGA and tissue microarray

Nuclear receptor FXR impairs SK‑Hep‑1 cell migration and invasion by inhibiting the Wnt/&beta;‑catenin signaling pathway

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Nuclear receptor FXR impairs SK‑Hep‑1 cell migration and invasion by inhibiting the Wnt/β‑catenin signaling pathway