Abstract 1310: Liver X receptor agonist blocks pancreatic cancer cell proliferation.

Abstract

Abstract 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