Department of Pathology, Chongqing Medical University, Chongqing, 400016, China.
Cell Death Dis. 2019 Mar 13;10(3):248. doi: 10.1038/s41419-019-1440-5.
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.
LXR-623（WAY-252623）是一种肝 X 受体激动剂，由于其具有穿透血脑屏障的能力，可减少动脉粥样硬化斑块的进展，并显著抑制神经胶质瘤细胞的增殖。然而，LXR-623 对其他癌细胞增殖的作用以及潜在的机制尚不清楚。长链非编码 RNA（lncRNA）作为新型关键调节因子，参与癌症的发生和多种生物学过程。在这里，我们报道了一种以前未被描述的机制，即 LXR-623 通过磷酸酶和张力蛋白同源物（PTEN）/蛋白激酶 B（AKT）/p53 轴介导的 lncRNA 外排作用，抑制体外癌细胞的增殖。我们发现 LXR-623 显著抑制了乳腺癌细胞的增殖，并呈浓度和时间依赖性诱导细胞凋亡和 S 期细胞周期阻滞。利用异种移植小鼠模型的实验揭示了 LXR-623 对肿瘤生长的抑制作用。我们使用 lncRNA 微阵列来研究可能受 LXR-623 调控的潜在基因。结果表明，LXR-623 处理的细胞中 LINC01125 显著上调。通过增益和缺失功能实验研究了 LINC01125 的抗增殖作用。LINC01125 敲低导致 LXR-623 的细胞毒性作用受到抑制；相反，LINC01125 过表达显著增强了 LXR-623 的作用。LXR-623 和 LINC01125 介导的抗生长调节作用至少部分与参与其中的 PTEN/AKT/鼠双微体 2 同源物（MDM2）/p53 通路有关。此外，SF1670，一种具有延长细胞内保留时间的特定 PTEN 抑制剂，可能强烈阻断 LXR-623 和 LINC01125 过表达诱导的抗增殖作用。染色质免疫沉淀（ChIP）实验结果表明，p53 结合 LINC01125 的启动子，以增强 PTEN/AKT 通路的表达。总之，我们的研究结果表明，LXR-623 在乳腺癌细胞中具有显著的抗肿瘤活性，部分是通过上调 LINC01125 的表达和增强细胞凋亡来实现的，而细胞凋亡是通过 PTEN/AKT/MDM2/p53 通路实现的。
