Liver X receptor reduces proliferation of human oral cancer cells by promoting cholesterol efflux via up-regulation of ABCA1 expression
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Tetsuharu Kaneko1,2,*, Chihiro Kanno1,2,*, Naoki Ichikawa-Tomikawa1,*, Korehito Kashiwagi1, Nanae Yaginuma1, Chihiro Ohkoshi1, Mizuko Tanaka1, Takashi Sugino3, Tetsuya Imura1, Hiroshi Hasegawa2, Hideki Chiba1
1Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan
2Division of Dentistry and Oral Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
3Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
*These authors have contributed equally to this work
Hideki Chiba, e-mail: [email protected]
Keywords: LXR, nuclear receptor, squamous cell carcinoma, cell growth, metabolism
Received: June 19, 2015 Accepted: September 18, 2015 Published: October 01, 2015
Liver X receptors (LXRs) contribute not only to maintain cholesterol homeostasis but also to control cell growth. However, the molecular mechanisms behind the LXR-mediated anti-proliferative effects are largely unknown. Here we show, by immunohistochemistry, that LXRα and LXRβ are differentially distributed in oral stratified squamous epithelia. By immunohistochemical and Western blot analyses, we also reveal that LXRα is abundantly expressed in human oral squamous cell carcinoma (HOSCC) tissues and cell lines. Cell counting, BrdU labeling and cell cycle assay indicated that LXR stimulation led to significant reduction of proliferation in HOSCC cells. Importantly, our study highlights, by using RNA interference, that the ATP-binding cassette transporter A1 (ABCA1)-accelerated cholesterol efflux is critical for the growth inhibitory action of LXRs in HOSCC cells. Moreover, we demonstrate that LXR activation reduces the growth of xenograft tumour of HOSCC cells in mice accompanied by the upregulation of ABCA1 expression and the decline of cholesterol levels in the tumour. These findings strongly suggested that targeting the LXR-regulated cholesterol transport, yielding in lowering intracellular cholesterol levels, could be a promising therapeutic option for certain types of cancers.
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