gw-3965 and Adenocarcinoma

Endometrial cancer (EC) is the most common gynaecological malignancy. Obesity is a major risk factor for EC and is associated with elevated cholesterol. 27-hydroxycholesterol (27HC) is a cholesterol metabolite that functions as an endogenous agonist for Liver X receptor (LXR) and a selective oestrogen receptor modulator (SERM). Exposure to oestrogenic ligands increases risk of developing EC; however, the impact of 27HC on EC is unknown. Samples of stage 1 EC (

Topics: Adenocarcinoma; Benzoates; Benzylamines; Cell Proliferation; Endometrial Neoplasms; Endometrium; Female; Humans; Hydroxycholesterols; Hysterectomy

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Benzoates; Benzylamines; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Female; Gemcitabine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Ligands; Liver X Receptors; Male; Microarray Analysis; Middle Aged; Neoplasm Proteins; Orphan Nuclear Receptors; Pancreatic Neoplasms; Signal Transduction