G protein‐coupled estrogen receptor is involved in modulating colonic motor function via nitric oxide release in C57<scp>BL</scp>/6 female mice

Li, Y; Xu, Jingyun; Jiang, Feng-Xian; Jiang, Zhe; Liu, C; Li, L; Luo, Yan; Lu, Ruirui; Mu, Yuguang; Liu, Yaoge; Xue, Bing

doi:10.1111/nmo.12743

Cited by 43 publications

(45 citation statements)

References 58 publications

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“…Immunohistochemical staining of GPER was similar in the colon and ileum. The latter finding is in line with results reported by Li et al., who detected expression of GPER in the proximal and distal colon of female mice (higher expression was detected in the proximal colon) . Our studies did not reveal differences in GPER distribution between males and females in the colon, leading us to suggest that disturbances in GPER expression implicated in GI disease development may affect both men and women.…”

Section: Discussionsupporting

confidence: 93%

“…The family of ERs includes (i) nuclear ERs (ERα and ERβ) and (ii) membrane mER‐Gαq, ER‐X, mERα, and mERβ, mediating genomic and non‐genomic action of ER ligands, respectively. G protein‐coupled estrogen receptor (GPER), also known as GPR30, belongs to the seven transmembrane G protein‐coupled receptor (GPCR) family and presents one site, which potentially mediates the effects of estrogen on GI motility . GPER is localized on the plasma membrane and on intracellular membranes, such as the endoplasmic reticulum and the Golgi apparatus .…”

Section: Introductionmentioning

confidence: 99%

“…G protein-coupled estrogen receptor (GPER), also known as GPR30, belongs to the seven transmembrane G protein-coupled receptor (GPCR) family and presents one site, which potentially mediates the effects of estrogen on GI motility. 15 GPER is localized on the plasma membrane and on intracellular membranes, such as the endoplasmic reticulum and the Golgi apparatus. 16 It was shown that 17β-estradiol is a highly potent agonist of GPER.…”

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confidence: 99%

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G protein‐coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain

Zielińska

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Bashashati

et al. 2017

Neurogastroenterology Motil

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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G protein‐coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain

Zielińska

Fichna

Bashashati

et al. 2017

Neurogastroenterology Motil

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“…For example, BMP4 and GPER are suppressed and induced, respectively, by effective compounds in COAD. BMP signalling promotes the growth of primary human colon carcinomas in vivo 32 and activation of GPER exerts an inhibitory effect on colonic motility33. Overexpression of RGS2 , a gene induced by effective compounds in BRCA, was reported to have an inhibitory effect on BRCA cell growth34.…”

Section: Resultsmentioning

confidence: 99%

Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets

et al. 2017

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The decreasing cost of genomic technologies has enabled the molecular characterization of large-scale clinical disease samples and of molecular changes upon drug treatment in various disease models. Exploring methods to relate diseases to potentially efficacious drugs through various molecular features is critically important in the discovery of new therapeutics. Here we show that the potency of a drug to reverse cancer-associated gene expression changes positively correlates with that drug’s efficacy in preclinical models of breast, liver and colon cancers. Using a systems-based approach, we predict four compounds showing high potency to reverse gene expression in liver cancer and validate that all four compounds are effective in five liver cancer cell lines. The in vivo efficacy of pyrvinium pamoate is further confirmed in a subcutaneous xenograft model. In conclusion, this systems-based approach may be complementary to the traditional target-based approach in connecting diseases to potentially efficacious drugs.

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“…As ERα and ERβ are not present in CRC, this suggests that estrogens may primarily act through GPER in CRC. Indeed, estrogen binding to GPER increases colonic transit time (Li et al, 2016) and is associated with pain severity in irritable bowel disease (Qin et al, 2014). However, this is the first report of GPER stimulation having a functional molecular consequence in STS activity.…”

Section: Discussionmentioning

confidence: 99%

Estrone Sulfate Transport and Steroid Sulfatase Activity in Colorectal Cancer: Implications for Hormone Replacement Therapy

et al. 2017

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Hormone replacement therapy (HRT) affects the incidence and potential progression of colorectal cancer (CRC). As HRT primarily consists of estrone sulfate (E1S), understanding whether this conjugated estrogen is transported and metabolized in CRC will define its potential effect in this malignancy. Here, we show that a panel of CRC cell lines (Colo205, Caco2, HCT116, HT-29) have steroid sulfatase (STS) activity, and thus can hydrolyze E1S. STS activity is significantly higher in CRC cell lysate, suggesting the importance of E1S transport in intracellular STS substrate availability. As E1S transport is regulated by the expression pattern of certain solute carrier organic anion transporter polypeptides, we show that in CRC OATP4A1 is the most abundantly expressed transporter. All four CRC cell lines rapidly transported E1S into cells, with this effect significantly inhibited by the competitive OATP inhibitor BSP. Transient knockdown of OATP4A1 significantly disrupted E1S uptake. Examination of estrogen receptor status showed ERα was present in Colo205 and Caco2 cells. None of the cells expressed ERβ. Intriguingly, HCT116 and HT29 cells strongly expressed the G protein coupled estrogen receptor (GPER), and that stimulation of this receptor with estradiol (E2) and G1, a GPER agonist, significantly (p < 0.01) increased STS activity. Furthermore, tamoxifen and fulvestrant, known GPER agonist, also increased CRC STS activity, with this effect inhibited by the GPER antagonist G15. These results suggest that CRC can take up and hydrolyze E1S, and that subsequent GPER stimulation increases STS activity in a potentially novel positive feedback loop. As elevated STS expression is associated with poor prognosis in CRC, these results suggest HRT, tamoxifen and fulvestrant may negatively impact CRC patient outcomes.

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G protein‐coupled estrogen receptor is involved in modulating colonic motor function via nitric oxide release in C57BL/6 female mice

Cited by 43 publications

References 58 publications

G protein‐coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain

G protein‐coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain

Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets

Estrone Sulfate Transport and Steroid Sulfatase Activity in Colorectal Cancer: Implications for Hormone Replacement Therapy

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