1. Academic Validation
  2. The LXR-623-induced long non-coding RNA LINC01125 suppresses the proliferation of breast cancer cells via PTEN/AKT/p53 signaling pathway

The LXR-623-induced long non-coding RNA LINC01125 suppresses the proliferation of breast cancer cells via PTEN/AKT/p53 signaling pathway

  • Cell Death Dis. 2019 Mar 13;10(3):248. doi: 10.1038/s41419-019-1440-5.
Weijun Wan 1 Yongying Hou 1 Ke Wang 1 Yue Cheng 1 Xia Pu 1 Xiufeng Ye 2
Affiliations

Affiliations

  • 1 Department of Pathology, Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Pathology, Chongqing Medical University, Chongqing, 400016, China. [email protected].
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.

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