Differential Regulation of EGFR–MAPK Signaling by Deoxycholic Acid (DCA) and Ursodeoxycholic Acid (UDCA) in Colon Cancer

Centuori, Sara; Martinez, Jesse D.

doi:10.1007/s10620-014-3190-7

Cited by 54 publications

(49 citation statements)

References 79 publications

(91 reference statements)

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“…One possible explanation is that BAs have different effects on normal bowel compared with colon cancer models, as we show inhibition of proliferation in a rodent injury model. Clearly, BAs differentially contribute to tumor progression (11). The variable doses used in different studies could also explain the discrepancies.…”

Section: Discussionmentioning

confidence: 99%

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Dossa

Escobar

Golden

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Dossa

Escobar

Golden

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Additionally, increased fecal DCA has also been implicated in the promotion of colon tumorigenesis. DCA was observed to induce colonic crypt cells proliferation and related to colon cancer growth and progression (48–50). Since chronic uncontrolled inflammation in the intestine is closely related to the development of colitis-associated cancer (CAC), our findings here suggest another possible mechanism that DCA participates in the development of colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice

et al. 2016

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A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (IBD). High-level fecal deoxycholic acid (DCA) caused by HFD contributes to the colonic inflammatory injury of IBD; however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation via promoting NLRP3 inflammasome activation. Here, we, for the first time, showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1β production in macrophages. Mechanistically, DCA-triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2. Colorectal instillation of DCA significantly increased mature IL-1β level in colonic tissue and exacerbated DSS-induced colitis, while in vivo blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1β production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high-level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contribute to HFD-related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of IBD.

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“…Secondary bile acids are considered potent tumour promoters, whereas the tertiary bile acid UDCA may act as a cytoprotective agent (Wild and Hardie, 2003). DCA and UDCA show distinctly different biological activities (Martinez et al, 1998;Centuori and Martinez, 2014). UDCA inhibits tumour development by countering the tumour-promoting effects of DCA.…”

Section: Introductionmentioning

confidence: 99%

Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells

Abdel-Latif

Inoue

Reynolds

2016

European Journal of Cancer Prevention

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Ursodeoxycholic acid (UDCA) was reported to reduce bile acid toxicity, but the mechanisms underlying its cytoprotective effects are not fully understood. The aim of the present study was to examine the effects of UDCA on the modulation of deoxycholic acid (DCA)-induced signal transduction in oesophageal cancer cells. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity was assessed using a gel shift assay. NF-κB activation and translocation was performed using an ELISA-based assay and immunofluorescence analysis. COX-2 expression was analysed by western blotting and COX-2 promoter activity was assessed by luciferase assay. DCA induced NF-κB and AP-1 DNA-binding activities in SKGT-4 and OE33 cells. UDCA pretreatment inhibited DCA-induced NF-κB and AP-1 activation and NF-κB translocation. This inhibitory effect was coupled with a blockade of IκB-α degradation and inhibition of phosphorylation of IKK-α/β and ERK1/2. Moreover, UDCA pretreatment inhibited COX-2 upregulation. Using transient transfection of the COX-2 promoter, UDCA pretreatment abrogated DCA-induced COX-2 promoter activation. In addition, UDCA protected oesophageal cells from the apoptotic effects of deoxycholate. Our findings indicate that UDCA inhibits DCA-induced signalling pathways in oesophageal cancer cells. These data indicate a possible mechanistic role for the chemopreventive actions of UDCA in oesophageal carcinogenesis.

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Differential Regulation of EGFR–MAPK Signaling by Deoxycholic Acid (DCA) and Ursodeoxycholic Acid (UDCA) in Colon Cancer

Cited by 54 publications

References 79 publications

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice

Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells

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