title: Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances cyclin D1 expression and promotes human endometrial cancer cell proliferation.
abstract: Endometrial cancer exhibits a strong incidence in western developed countries mainly due to fat-rich diet and obesity. Processing of dietary lipids is triggered by bile acids, amphipathic detergents that are synthesized in the liver and stored in the gallbladder. In addition to their well-recognized role in dietary lipid absorption and cholesterol homeostasis, bile acids can also act as signaling molecules with systemic endocrine functions.   In the present study we investigated the biological effects of the primary bile chenodeoxycholic acid (CDCA) on a human endometrial cancer cell line, Ishikawa. Low concentrations of CDCA are able to stimulate Ishikawa cell growth by inducing a significant increase in Cyclin D1 protein and mRNA expression through the activation of the membrane G protein-coupled receptor (TGR5)-dependent pathway. Dissecting the molecular mechanism underlying this effect by mutagenesis, EMSA and ChIP analysis revealed that CDCA-induced Cyclin D1 expression requires the enhanced recruitment of the transcription factor CREB on the cyclic AMP-responsive element motif within the Cyclin D1 gene proximal promoter.   Our results suggest a novel molecular mechanism explaining the potential contribution of high-fat diet and obesity to endometrial cancer growth and progression opening the rationale for strategies to prevent the risk of this obesity-related cancer in women.
authors: Department of Pharmaco-Biology, University of Calabria, Cosenza, Italy. icasaburi@yahoo.it
authors: Ivan
authors: I
authors: Casaburi
authors: Paola
authors: P
authors: Avena
authors: Marilena
authors: M
authors: Lanzino
authors: Diego
authors: D
authors: Sisci
authors: Francesca
authors: F
authors: Giordano
authors: Pamela
authors: P
authors: Maris
authors: Stefania
authors: S
authors: Catalano
authors: Catia
authors: C
authors: Morelli
authors: Sebastiano
authors: S
authors: Andò
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C473772:GPBAR1 protein, human; D005765:Gastrointestinal Agents; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D002635:Chenodeoxycholic Acid; D019938:Cyclin D1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3