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Targeting newly identified ER?/TGF-?1/SMAD3 signals with the FDA-approved anti-estrogen Faslodex or an ER? selective antagonist in renal cell carcinoma.

ABSTRACT: Renal cell carcinoma (RCC) has the third highest mortality rate among urological tumors, and 20-30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor ? (ER?) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified. In the present study, we found that expression of ER?, but not ER?, increases with tumor stage and grade, and also observed that modification of ER? signals using estrogens/anti-estrogens, shRNA knockdown of ER? and overexpression of ER? using ectopic cDNA affects RCC cell proliferation, migration and invasion. Mechanism analysis revealed that ER? can promote RCC cell invasion via an increase in transforming growth factor ?1 (TGF-?1)/SMAD3 signals, and interrupting TGF-?1/SMAD3 signals with a TGF?R1 inhibitor can reverse/block ER?-increased RCC cell migration. Importantly, preclinical analyses using in vivo mouse models of RCC revealed that targeting of this newly identified ER?/TGF-?1/SMAD3 pathway with either the FDA-approved anti-estrogen ICI182,780 (Faslodex) or a selective ER? antagonist 4-[2-phenyl-5,7 bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol can significantly reduce RCC tumor growth and invasion, which may be suitable as the basis for novel therapies to more effectively suppress metastatic RCC.

SUBMITTER: Song W

PROVIDER: S-EPMC6275262 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Targeting newly identified ERβ/TGF-β1/SMAD3 signals with the FDA-approved anti-estrogen Faslodex or an ERβ selective antagonist in renal cell carcinoma.

Song Wenbin W He Dalin D Chen Yule Y Yeh Chiuan-Ren CR Hsu Iawen I Huang Qingbo Q Zhang Xu X Chang Luke Sien-Shih LS Zuo Li L Chen Jiasheng J Doersch Karen M KM Chang Chawnshang C Li Lei L Yeh Shuyuan S

Molecular oncology 20181030 12

Renal cell carcinoma (RCC) has the third highest mortality rate among urological tumors, and 20-30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor β (ERβ) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified. In the present study, we found that expression of ERβ, but not ERα, increases with tumor stage and grade, and also observed that modification of ERβ signals using es ...[more]

PMID: 30171816

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Project description:PurposeTo assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.MethodsAlbino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections.ResultsA five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice.ConclusionsIntraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

Project description:Transforming growth factor-beta1 (TGF-β1) is a major factor in pathogenesis of chronic hepatic injury. Carbon tetrachloride (CCl4) is a liver toxicant, and CCl4-induced liver injury in mouse is a classical animal model of chemical liver injury. However, it is still unclear whether TGF-β1 is involved in the process of CCl4-induced acute chemical liver injury. The present study aimed to evaluate the role of TGF-β1 and its signaling molecule Smad3 in the acute liver injury induce by CCl4. The results showed that CCl4 induced acute liver injury in mice effectively confirmed by H&E staining of liver tissues, and levels of not only liver injury markers serum ALT and AST, but also serum TGF-β1 were elevated significantly in CCl4-treated mice, compared with the control mice treated with olive oil. Our data further revealed that TGF-β1 levels in hepatic tissue homogenate increased significantly, and type II receptor of TGF-β (TβRII) and signaling molecules Smad2, 3, mRNA expressions and Smad3 and phospho-Smad3 protein levels also increased obviously in livers of CCl4-treated mice. To clarify the effect of the elevated TGF-β1/Smad3 signaling on CCl4-induced acute liver injury, Smad3 in mouse liver was overexpressed in vivo by tail vein injection of Smad3-expressing plasmids. Upon CCl4 treatment, Smad3-overexpressing mice showed more severe liver injury identified by H&E staining of liver tissues and higher serum ALT and AST levels. Simultaneously, we found that Smad3-overexpressing mice treated with CCl4 showed more macrophages and neutrophils infiltration in liver and inflammatory cytokines IL-1β and IL-6 levels increment in serum when compared with those in control mice treated with CCl4. Moreover, the results showed that the apoptosis of hepatocytes increased significantly, and apoptosis-associated proteins Bax, cytochrome C and the cleaved caspase 3 expressions were up-regulated in CCl4-treated Smad3-overexpressing mice as well. These results suggested that TGF-β1/Smad3 signaling was activated during CCl4-induced acute liver injury in mice, and Smad3 overexpression aggravated acute liver injury by promoting inflammatory cells infiltration, inflammatory cytokines release and hepatocytes apoptosis. In conclusion, the activation of TGF-β signaling contributes to the CCl4-induced acute liver injury. Thus, TGF-β1/Smad3 may serve as a potential target for acute liver injury therapy.

Dataset Information

Targeting newly identified ER?/TGF-?1/SMAD3 signals with the FDA-approved anti-estrogen Faslodex or an ER? selective antagonist in renal cell carcinoma.

Publications

Targeting newly identified ERβ/TGF-β1/SMAD3 signals with the FDA-approved anti-estrogen Faslodex or an ERβ selective antagonist in renal cell carcinoma.

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