Sulfated alginate oligosaccharide exerts antitumor activity and autophagy induction by inactivating MEK1/ERK/mTOR signaling in a KSR1-dependent manner in osteosarcoma.
Sulfated alginate oligosaccharide exerts antitumor activity and autophagy induction by inactivating MEK1/ERK/mTOR signaling in a KSR1-dependent manner in osteosarcoma.
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硫酸化海藻酸寡糖通过 KSR1 依赖性方式灭活 MEK1/ERK/mTOR 信号传导，在骨肉瘤中发挥抗肿瘤活性和自噬诱导作用
DOI：
10.1038/s41389-022-00390-x
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发表时间：
2022-04-13
期刊：
影响因子：
6.2
通讯作者：
Cheng, Dong-dong
中科院分区：
文献类型：
--
作者：
Pan, Zhen;Wei, Xiao-juan;Li, Shi-jie;Guo, Hua;Li, Zhao-hui;Zhang, Ke-ke;Lyu, Qian-qian;Liu, Wei-zhi;Yang, Qing-cheng;Cheng, Dong-dong
海藻酸低聚糖(AOS)具有抑制肿瘤进展的作用，硫酸酯修饰可增强其抗肿瘤活性。到目前为止，硫酸化AOS(AOS-SO4)在肿瘤中的作用和机制在很大程度上仍不清楚。我们用酶法降解海藻酸盐制备AOS-SO4，按照规范的程序进行硫酸盐化制备AOS-SO4。使用这些材料，体外实验表明，AOS和AOS-SO4都能在骨肉瘤细胞中产生抗肿瘤作用。硫酸化修饰显著提高了其抗肿瘤活性。此外，AOS-SO4在体内外均具有明显的细胞周期停滞、细胞凋亡和自噬诱导作用。从机制上，我们观察到AOS-SO4处理通过抑制MEK1/ERK/mTOR信号而触发了促凋亡自噬。ERK激活剂逆转了AOS-SO4诱导的自噬。更重要的是，我们发现在骨肉瘤细胞中，KSR1与MEK1相互作用，并作为MEK1蛋白的正调控因子发挥作用。在骨肉瘤患者中，KSR1的高表达与生存不良显著相关。综上所述，AOS-SO4通过抑制依赖于KSR1的MEK1/ERK/mTOR信号通路，在骨肉瘤中具有较好的抗肿瘤作用，有望成为治疗骨肉瘤的新的候选药物。
Alginate oligosaccharide (AOS) has the function to inhibit tumor progression and the sulfated modification can enhance the antitumor activity. To date, the function and mechanism of sulfated AOS (AOS-SO4) in tumors remain largely elusive. We prepared AOS by the enzymatic degradation of alginate, collected AOS-SO4 by sulfating following the canonical procedure. Using these materials, in vitro assays showed that both AOS and AOS-SO4 elicited antitumor effects in osteosarcoma cells. Sulfated modification significantly enhanced the antitumor activity. In addition, AOS-SO4 had obvious effects on cell cycle arrest, apoptosis, and autophagy induction in vitro and in vivo. Mechanistically, we observed that AOS-SO4 treatment triggered proapoptotic autophagy by inhibiting MEK1/ERK/mTOR signaling. The ERK activator reversed AOS-SO4-induced autophagy. More importantly, we found that KSR1 interacted with MEK1 and functioned as a positive regulator of MEK1 protein in osteosarcoma cells. High KSR1 expression was significantly associated with poor survival in osteosarcoma patients. Together, these results suggest that AOS-SO4 has a better antitumor effect in osteosarcoma by inhibiting MEK1/ERK/mTOR signaling, which is KSR1-dependent; thus, AOS-SO4 can be a new potential therapeutic candidate for the treatment of osteosarcoma.
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