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.
Highlights
Breast cancer (BC) is one of the most common cancers and accounts for about 30% of the cancer cases in females worldwide
We found that Liver X receptors (LXRs)-623 significantly suppressed the viability of MCF-7, MDA-MB-231, BT549, and MDAMB-453 cells in a dose- and time-dependent manner (Fig. 1a)
We tested the expression of apoptosis-related proteins by western blot analysis and found that the expression of activated caspase-3 and BAX was upregulated and that of B-cell lymphoma 2 (BCL2) was downregulated in a timedependent manner (Fig. 1d)
Summary
Breast cancer (BC) is one of the most common cancers and accounts for about 30% of the cancer cases in females worldwide It is ranked as the second most common cause of cancer-related deaths[1,2]. Liver X receptors (LXRs) are nuclear receptors that induce the expression of the transporters responsible for promoting cholesterol efflux, leading to the reduction in atherosclerosis. Recent reports have revealed that blastic plasmacytoid dendritic neoplasm cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation in the expression of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1, in response to LXR agonist treatment[8]. LXR agonist may regulate the progression of prostate cancer through suppressor of cytokine signaling 39 and reduce protein kinase B (Akt) phosphorylation in BC10. Little is known about the antitumor impact of LXR-623 on other cancers
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