Abstract
LXR-623 (WAY-252623), a liver X receptor agonist, reduces atherosclerotic plaque progression and remarkably inhibits the proliferation of glioblastoma cells, owing to its brain-penetrant ability. However, the role of LXR-623 against the proliferation of other cancer cells and the underlying mechanism remain unknown. Long non-coding RNAs (lncRNAs) serve as novel and crucial regulators that participate in cancer tumorigenesis and diverse biological processes. Here, we report a previously uncharacterized mechanism underlying lncRNA-mediated exocytosis of LXR-623 via the phosphatase and tensin homolog (PTEN)/protein kinase B (AKT)/p53 axis to suppress the proliferation of cancer cells in vitro. We found that LXR-623 significantly inhibited the proliferation and induced apoptosis and cell cycle arrest at S phase in breast cancer cells in a concentration- and time-dependent manner. Experiments using a xenograft mouse model revealed the inhibitory effects of LXR-623 on tumor growth. We used lncRNA microarray to investigate the potential genes regulated by LXR-623. As a result, LINC01125 was found to be significantly upregulated in the cells treated with LXR-623. Gain- and loss-of-function assays were conducted to investigate the anti-proliferation role of LINC01125. LINC01125 knockdown resulted in the inhibition of the cytotoxic effect of LXR-623; in contrast, LINC01125 overexpression significantly enhanced the effect of LXR-623. LXR-623 and LINC01125-mediated anti-growth regulation is, at least in part, associated with the participation of the PTEN/AKT/mouse double minute 2 homolog (MDM2)/p53 pathway. In addition, SF1670, a specific PTEN inhibitor with prolonged intracellular retention, may strongly block the anti-proliferation effect induced by LXR-623 and LINC01125 overexpression. Chromatin immunoprecipitation (ChIP) assay results suggest that p53 binds to the promoter of LINC01125 to strengthen the expression of the PTEN/AKT pathway. Taken together, our findings suggest that LXR-623 possesses significant antitumor activity in breast cancer cells that is partly mediated through the upregulation in LINC01125 expression and enhancement in apoptosis via the PTEN/AKT/MDM2/p53 pathway.