Overactivation of Wnt/β-catenin pathway due to dysfunction of retinoid-related orphan receptor α (RORα) is related to cancer development and progression. Diallyl disulfide (DADS), an active component of garlic, has been reported in our previous study for upregulation of RORα expression in gastric cancer (GC) cells. It remains to be elucidated the role and mechanism of RORα in DADS against GC. This study revealed that DADS treatment resulted in reduced expression levels of Wnt1, β-catenin, TCF-4, intranuclear β-catenin and p-β-catenin in GC cells, concomitant with the compromised expression of β-catenin target genes (Axin, c-Jun, and c-Myc). RORα overexpression augmented DADS-induced downregulation of Wnt1/β-catenin pathway, G2/M phase arrest, and cell growth inhibition in vitro and in vivo. Contrarily, knockdown of RORα attenuated these effects of DADS. Interestingly, DADS induced an increase in the binding of RORα to β-catenin, which may lead to reduction of β-catenin phosphorylation and nuclear translocation. This interplay modulated by DADS may affect β-catenin target gene expression for that the opposite results were observed in DADS-treated RORα knockdown and overexpression cells. DADS caused a decrease in vimentin, snail and MMP-9, as well as an increase in E-cadherin and TIMP3 expression, which restricted epithelial–mesenchymal transition (EMT), migration, and invasion. The aforementioned effects of DADS were weakened simultaneously when the suppression of DADS on the Wnt1/β-catenin pathway was resisted by knockdown of RORα. In contrast, overexpression of RORα enhanced the effects of DADS. Therefore, RORα-mediated downregulation of Wnt1/β-catenin pathway could undertake an important role in anticancer activity of DADS against GC cell proliferation, EMT, migration, and invasion.

由于类维生素A相关孤儿受体α（RORα）功能障碍导致Wnt/β-连环蛋白通路过度激活，与癌症的发生和进展有关。我们之前的研究报道了大蒜的活性成分二烯丙基二硫化物（DADS）可以上调胃癌（GC）细胞中的 RORα 表达。RORα在DADS抗GC中的作用和机制仍有待阐明。这项研究表明，DADS 处理导致 GC 细胞中 Wnt1、β-catenin、TCF-4、核内 β-catenin 和 p-β-catenin 的表达水平降低，同时 β-catenin 靶基因（Axin、 c-Jun 和 c-Myc)。RORα 过表达增强了 DADS 诱导的 Wnt1/β-catenin 通路下调、G2/M 期停滞以及体外和体内细胞生长抑制。相反，RORα 的敲低减弱了 DADS 的这些作用。有趣的是，DADS 诱导 RORα 与 β-连环蛋白的结合增加，这可能导致 β-连环蛋白磷酸化和核易位减少。DADS 调节的这种相互作用可能会影响 β-catenin 靶基因的表达，因为在 DADS 处理的 RORα 敲低和过表达细胞中观察到相反的结果。DADS 导致波形蛋白、snail 和 MMP-9 减少，以及 E-钙粘蛋白和 TIMP3 表达增加，从而限制上皮间质转化 (EMT)、迁移和侵袭。当通过敲低 RORα 来抵抗 DADS 对 Wnt1/β-catenin 通路的抑制时，DADS 的上述作用同时减弱。相反，RORα 的过度表达增强了 DADS 的效果。所以，