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.

Pancreatic cancer is the fourth leading cause of cancer deaths in the US and has the worst prognosis of the major cancers due to difficulties in early detection and limited treatment options. Nuclear receptors (NRs) are a family of ligand-dependent transcription factors which play key roles in regulating gene expression in normal development and physiology and in a number of human diseases, including cancers. These receptors and their ligands are involved in breast and prostate cancers, and they have been successfully targeted clinically in the prevention and treatment of these diseases. Liver X receptors (LXRs) are NRs which are known to regulate cholesterol, glucose, and fatty acid metabolism and inflammatory responses. Published reports of the ability of LXR agonists to block the growth and proliferation of breast, prostate, ovarian, lung, skin, and colorectal cancer cells suggest that LXRs are involved in regulating common pathways in cancer progression and tumor cell growth and proliferation found in these diverse cancers and perhaps other malignancies as well. To test this hypothesis, we treated pancreatic cancer cells (PANC-1, Mia-PaCa-2, and BxPC-3) with the synthetic LXR ligand GW3965, originally developed for the treatment of atherosclerosis, and measured the effects of ligand treatment on cell proliferation, survival, and cell cycle progression. Treatment with the LXR ligand disrupted cell proliferation as determined by trypan blue exclusion, clonogenic, bromodeoxyuridine incorporation, and tetrazolium salt reduction assays. Cell cycle analysis indicated an increase in cells in the G0 or G1 phase, suggestive of cell cycle arrest or withdrawal. To determine potential mechanisms underlying the observed effects, we performed microarray analysis of gene expression in response to ligand treatment and found that known LXR target genes and genes associated with a number of signaling pathways and molecular processes, including those involved in cell division, are differentially expressed in pancreatic cancer cells following treatment. These findings suggest that LXRs and their ligands target gene networks which are important for pancreatic cancer cell proliferation and warrant further study as potential therapeutic targets and agents, respectively, in the treatment of pancreatic cancer. Citation Format: Nicholes R. Candelaria, Sridevi Manchem, H Trang Vu, Jine Zheng, Chiara Gabbi, Prasenjit Dey, Husna Karaboga, Jean Lin, Lise-Lotte Vedin, Fei Su, Ka Liu, Philip Jonsson, Knut R. Steffensen, Jan-Åke Gustafsson, Chin-Yo Lin. Liver X receptor agonist blocks pancreatic cancer cell proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1310. doi:10.1158/1538-7445.AM2013-1310