Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer.
Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer.
复制标题
DOI：
10.1038/srep44990
复制
发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Wu YC
中科院分区：
文献类型：
--
作者：
Hsu HY;Lin TY;Lu MK;Leng PJ;Tsao SM;Wu YC
褐藻糖胶是一种从褐藻中提取的硫酸化多糖，具有抗癌活性。然而，岩藻依聚糖通过内质网（ER）应激诱导细胞凋亡的作用和机制尚不清楚。在这项研究中，我们证明岩藻依聚糖可预防 LLC1 异种移植雄性 C57BL/6 小鼠的肿瘤发生并减小肿瘤大小。褐藻糖胶通过激活 PERK-ATF4-CHOP 途径诱导 ER 应激反应，导致体外和体内细胞凋亡。此外，ATF4 敲低可消除岩藻依聚糖诱导的 CHOP 表达并挽救细胞活力。具体来说，岩藻依聚糖可增加细胞内活性氧 (ROS)，从而增加肺癌细胞中的 ATF4 和 CHOP。使用ROS清除剂N-乙酰-L-半胱氨酸（NAC），我们发现ROS的产生参与岩藻依聚糖诱导的内质网应激介导的细胞凋亡。此外，通过敲低 Toll 样受体 4 (TLR4)，我们证明岩藻依聚糖诱导的 ROS 和 CHOP 表达减弱。我们的研究首次确定了岩藻依聚糖抗肿瘤活性的新机制。我们发现岩藻依聚糖通过激活 TLR4/ROS/ER 应激轴和下游 PERK-ATF4-CHOP 通路来抑制肿瘤活力，从而导致细胞凋亡并抑制肺癌细胞进展。总之，这些结果表明岩藻依聚糖是一种潜在的肺癌预防和治疗剂，通过激活 ROS 依赖性内质网应激途径发挥作用。
Fucoidan, a sulfated polysaccharide extracted from brown algae, exhibits anti-cancer activity. However, the effects and mechanism of fucoidan-induced apoptosis via endoplasmic reticulum (ER) stress is unclear. In this study, we demonstrated that fucoidan prevents tumorigenesis and reduces tumor size in LLC1-xenograft male C57BL/6 mice. Fucoidan induces an ER stress response by activating the PERK-ATF4-CHOP pathway, resulting in apoptotic cell death in vitro and in vivo. Furthermore, ATF4 knockdown abolishes fucoidan-induced CHOP expression and rescues cell viability. Specifically, fucoidan increases intracellular reactive oxygen species (ROS), which increase ATF4 and CHOP in lung cancer cells. Using the ROS scavenger N-acetyl-l-cysteine (NAC), we found that ROS generation is involved in fucoidan-induced ER stress-mediated apoptosis. Moreover, via Toll-like receptor 4 (TLR4) knockdown, we demonstrated that fucoidan-induced ROS and CHOP expression were attenuated. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan. We showed that fucoidan inhibits tumor viability by activating the TLR4/ROS/ER stress axis and the downstream PERK-ATF4-CHOP pathway, leading to apoptosis and suppression of lung cancer cell progression. Together, these results indicate that fucoidan is a potential preventive and therapeutic agent for lung cancer that acts via activation of ROS-dependent ER stress pathways.