Liver X Receptor (LXR) Activation Decreases Chronic Myelogenous Leukemia Cell Viability and Alters the Expression of Antiapoptotic and Cholesterol Genes

Abstract

Liver X receptors (LXRs) are oxysterol‐activated nuclear receptors involved in the regulation of cholesterol transport, glucose metabolism, and inflammatory responses. Recently, LXRs have been shown to possess anti‐cancer effects in a variety of cancer types, in part due its capacity to deplete essential lipids required for cell proliferation. However, the role of LXRs in chronic myelogenous leukemia (CML) has yet to be elucidated. In this study, we investigated the effects of LXR activation on the human erythroleukemia K562 cell line – a model for CML. K562 cells were treated with the LXR agonist TO901317 (0μM, 1μM, 5μM, 10μM) to determine dose‐ and time‐dependent effects on cell viability, cell number and size, and the mRNA expression of genes related to cholesterol metabolism (ATP‐binding cassette transporter A1 (ABCA1), low‐density lipoprotein receptor (LDLR), and HMG‐CoA reductase (HMGCR)) and anti‐apoptosis (B cell leukemia‐xL (Bcl‐xL)). TO901317 treatment significantly increased ABCA1 mRNA expression at 24hr and 72hr, with greater expression at the lowest treatment concentration (1μM). HMGCR and Bcl‐xL mRNA expression was dose‐dependently reduced by LXR activation after 72hr, as were decreases in total cell number. Average cell size similarly decreased from 24hr to 72hr with 10μM TO901317 treatment. Further, K562 viability was decreased by TO901317 treatment at all concentrations at 24hr, 48hr, and 72hr, with dose‐dependent effects observed at 48hr only. Together, these findings suggest that LXR agonism decreases CML cell viability and number, and that these changes may be related to modulation of cholesterol metabolism and apoptotic pathways. Current studies are underway to further investigate these pathways, in addition to the capacity of TO901317‐induced LXR activation to modulate cellular differentiation.Support or Funding InformationThe Science Institute of the College of Arts and Sciences and Faculty Research Committee, Fairfield University