gsk1210151a and Carcinoma--Pancreatic-Ductal

The fibrotic reaction, which can account for over 70%-80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs. We show that the inhibitory effect of pan-BET inhibitors on collagen I expression in primary cancer-associated PSCs is through blocking of BRD4 function. Importantly, we show that FOSL1 is repressed by BRD4 in primary cancer-associated PSCs and negatively regulates collagen I expression. While BET inhibitors do not affect viability or induce PSC apoptosis or senescence, BET inhibitors induce primary cancer-associated PSCs to become quiescent. Finally, we show that BET inhibitors attenuate stellate cell activation, fibrosis, and collagen I production in the EL-Kras

Topics: Animals; Azepines; Carcinoma, Pancreatic Ductal; Cell Cycle Proteins; Cell Line, Tumor; Collagen Type I; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 4 or More Rings; Humans; Mice; Nuclear Proteins; Pancreatic Neoplasms; Pancreatic Stellate Cells; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins p21(ras); RNA-Binding Proteins; Transcription Factors; Triazoles; Xenograft Model Antitumor Assays