Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances Cyclin D1 expression and promotes human endometrial cancer cell proliferation

Casaburi, Ivan; Avena, Paola; Lanzino, Marilena; Sisci, Diego; Giordano, Francesca; Maris, Pamela; Catalano, Stefania; Morelli, Catia; Andò, Sebastiano

doi:10.4161/cc.21029

Cited by 69 publications

(50 citation statements)

References 30 publications

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“…Some of these gene nodes have been shown to be functionally involved in other cancer types, including regulation of tumor cell proliferation (Creb, C/ebp, ATF3, ATF4) [72]–[75], invasion (MTHFD2, FGF2) [76], [77] and metastasis (PTGS1/COX1, E-selectin, ATF3, FGF2, IL1A, MMP1, MMP13) [78]–[83]. Thus, our data support the concept of oncogenic role of RUNX2 in EOC, and support previous findings for its rather universal functions in tumorigenesis, including tumor invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RUNX2 Transcriptional Activity Blocks the Proliferation, Migration and Invasion of Epithelial Ovarian Carcinoma Cells

et al. 2013

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Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from serous epithelial ovarian cancer (EOC) patients, when compared to primary cultures derived from matched primary (prior to CT) tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic) stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to a sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced.Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in serous EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of RUNX2 Transcriptional Activity Blocks the Proliferation, Migration and Invasion of Epithelial Ovarian Carcinoma Cells

et al. 2013

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“…54 For DAX-1 gene silencing experiments, custom synthesized siRNA (Ambion) annealed duplexes were used for effective depletion of DAX-1 mRNA. Scrambled siRNA is used as a control for non-sequence-specific effects.…”

Section: Methodsmentioning

confidence: 99%

DAX-1, as an androgen-target gene, inhibits aromatase expression: a novel mechanism blocking estrogen-dependent breast cancer cell proliferation

et al. 2013

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Sexual hormones, estrogens and androgens, determine biological response in a tissue- and gender-specific manner and have a pivotal role in endocrine-mediated tumorigenesis. In situ estrogen production by aromatase is a critical determinant for breast cancer growth and progression. On the contrary, clinical and in vitro studies indicate that androgens have a protective role in mammary carcinogenesis. Here, we demonstrated, in hormone-dependent breast cancer cells, the existence of a functional interplay between the androgen receptor (AR), the orphan nuclear receptor DAX-1 and the aromatase enzyme involved in the inhibition of the estrogen-dependent breast cancer cell proliferation exerted by androgen signaling. Indeed, our results revealed, in MCF-7 cells, that ligand-activated AR induces the expression of the orphan nuclear receptor DAX-1 by direct binding to a newly identified androgen-response-element within the DAX-1 proximal promoter. In turn, androgen-induced DAX-1 is recruited, in association with the corepressor N-CoR, within the SF-1/LRH-1 containing region of the aromatase promoter, thereby repressing aromatase expression and activity. In elucidating a novel mechanism by which androgens, through DAX-1, inhibit aromatase expression in breast cancer cell lines, these findings reinforce the theory of androgen- opposing estrogen-action, opening new avenues for therapeutic intervention in estrogen-dependent breast tumors.

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“…GPCRs are the most common targets of modern drug discovery [41]. A downside of TGR5 is the fact that a lot of functions are still unknown or could be interpreted as undesired side effects, such as itching, defecation, growth of cancer cells and pancreatitis [16,25,[43][44][45][46]. The observations described in the present review suggest that these TGR5 ligands may be useful as drugs to treat chronic inflammatory diseases as well, including atherosclerosis.…”

Section: Discussionmentioning

confidence: 76%

TGR5 in inflammation and cardiovascular disease

Pols

2014

Biochemical Society Transactions

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TGR5 (Takeda G-protein-coupled receptor 5) [also known as GPBAR1 (G-protein-coupled bile acid receptor 1), M-BAR (membrane-type receptor for bile acids) or GPR131 (G-protein-coupled receptor 131)] is a G-protein-coupled receptor that was discovered as a bile acid receptor. TGR5 has specific roles in several tissues, among which are the regulation of energy expenditure, GLP-1 (glucagon-like peptide 1) secretion and gall bladder filling. An accumulating body of evidence now demonstrates that TGR5 also acts in a number of processes important in inflammation. Most striking in this context are several observations that TGR5 signalling curbs the inflammatory response of macrophages via interfering with NF-κB (nuclear factor κB) activity. In line with this, recent animal studies also suggest that TGR5 could be exploited as a potential target for intervention in a number of inflammation-driven diseases, including atherosclerosis. In the present paper, I review our current understanding of TGR5 with a strong focus on its potential as target for intervention in inflammation-driven diseases.

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Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances Cyclin D1 expression and promotes human endometrial cancer cell proliferation

Cited by 69 publications

References 30 publications

Inhibition of RUNX2 Transcriptional Activity Blocks the Proliferation, Migration and Invasion of Epithelial Ovarian Carcinoma Cells

Inhibition of RUNX2 Transcriptional Activity Blocks the Proliferation, Migration and Invasion of Epithelial Ovarian Carcinoma Cells

DAX-1, as an androgen-target gene, inhibits aromatase expression: a novel mechanism blocking estrogen-dependent breast cancer cell proliferation

TGR5 in inflammation and cardiovascular disease

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