Department of Pathology, Dokkyo Medical University School of Medicine and Graduate School of Medicine, Mibu, Japan;
Department of Pathology, Dokkyo Medical University School of Medicine and Graduate School of Medicine, Mibu, Japan.
Anticancer Res. 2022 Jun;42(6):2923-2930. doi: 10.21873/anticanres.15774.
BACKGROUND/AIM: Liver X receptors (LXRs) are nuclear receptors with various functions, including the regulation of cholesterol metabolism, glucose homeostasis, and inflammation. We previously reported that LXR activation inhibits the growth of oral cancer cells by inducing cellular cholesterol efflux and that LXRβ is expressed mainly in small-cell lung cancer (SCLC) tissues. SCLC is one of the most aggressive cancers, and identifying an effective therapeutic target molecule is desirable. Therefore, we investigated whether LXRβ could be an effective target molecule for SCLC treatment through in vitro experiments.
We evaluated the influence of treatment with the LXR agonist T0901317 on cell proliferation and apoptosis in SCLC cell lines using cell viability, BrdU-ELISA, FACS, and western blot analyses. Moreover, the mechanism by which T0901317 inhibits SCLC cell proliferation was elucidated using qRT-PCR, western blot, a cholesterol quantification assay, and a genome editing technique.
We showed that cultivated SCLC cells expressed LXRβ and that an LXR agonist inhibited the proliferation of SCLC cells without toxicity to normal cells. Furthermore, the antitumoral effect of an LXR agonist on SCLC cells was attributed to the induction of ABCA1 by LXRβ activation, resulting in an increase in cellular cholesterol efflux via ABCA1.
The activation of LXRβ up-regulates ABCA1 expression, causing cholesterol depletion in cancer cells. This mechanism could be a novel target strategy for SCLC.
背景/目的：肝 X 受体（LXRs）是具有多种功能的核受体，包括调节胆固醇代谢、葡萄糖稳态和炎症。我们之前报道过，LXR 的激活通过诱导细胞内胆固醇外流来抑制口腔癌细胞的生长，并且 LXRβ 主要在小细胞肺癌（SCLC）组织中表达。SCLC 是最具侵袭性的癌症之一，因此，我们希望确定有效的治疗靶点分子。因此，我们通过体外实验研究了 LXRβ 是否可以成为治疗 SCLC 的有效靶点分子。
我们使用细胞活力、BrdU-ELISA、FACS 和 Western blot 分析评估了 LXR 激动剂 T0901317 处理对 SCLC 细胞系细胞增殖和凋亡的影响。此外，我们使用 qRT-PCR、Western blot、胆固醇定量测定和基因组编辑技术阐明了 T0901317 抑制 SCLC 细胞增殖的机制。
我们表明，培养的 SCLC 细胞表达 LXRβ，LXR 激动剂抑制 SCLC 细胞的增殖而对正常细胞没有毒性。此外，LXR 激动剂对 SCLC 细胞的抗肿瘤作用归因于 LXRβ 激活诱导 ABCA1 的表达，从而通过 ABCA1 增加细胞内胆固醇外流。
LXRβ 的激活上调 ABCA1 的表达，导致癌细胞中的胆固醇耗竭。这种机制可能成为 SCLC 的一种新的靶点策略。
