State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
NHC Key Laboratory of Biotechnology of Antibiotics, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Tiantan Xili, Beijing 100050, China.
Cells. 2024 Apr 3;13(7):620. doi: 10.3390/cells13070620.
Cancer stem cells (CSCs) are closely associated with tumor initiation, metastasis, chemoresistance, and recurrence, which represent some of the primary obstacles to cancer treatment. Targeting CSCs has become an important therapeutic approach to cancer care. Secoemestrin C (Sec C) is a natural compound with strong anti-tumor activity and low toxicity. Here, we report that Sec C effectively inhibited colorectal CSCs and non-CSCs concurrently, mainly by inhibiting proliferation, self-renewal, metastasis, and drug resistance. Mechanistically, RNA-seq analysis showed that the pro-inflammation pathway of the IL17 axis was enriched, and its effector S100A8 was dramatically decreased in Sec C-treated cells, whose roles in the stemness of CSCs have not been fully clarified. We found that the overexpression of S100A8 hindered the anti-CSCs effect of Sec C, and S100A8 deficiency attenuated the stemness traits of CSCs to enhance the Sec C killing activity on them. Meanwhile, the p38 signal pathway, belonging to the IL17 downstream axis, can also mediate CSCs and counter with Sec C. Notably, we found that S100A8 upregulation increased the p38 protein level, and p38, in turn, promoted S100A8 expression. This indicated that p38 may have a mutual feedback loop with S100A8. Our study discovered that Sec C was a powerful anti-colorectal CSC agent, and that the positive feedback loop of p38-S100A8 mediated Sec C activity. This showed that Sec C could act as a promising clinical candidate in colorectal cancer treatment, and S100A8 could be a prospective drug target.
癌症干细胞（CSC）与肿瘤起始、转移、化疗耐药和复发密切相关，这些是癌症治疗的主要障碍。针对 CSC 已成为癌症治疗的重要治疗方法。Secoemestrin C（Sec C）是一种具有强抗肿瘤活性和低毒性的天然化合物。在这里，我们报告 Sec C 可有效抑制结直肠 CSC 和非 CSC，主要通过抑制增殖、自我更新、转移和耐药性。机制上，RNA-seq 分析表明，IL17 轴的促炎途径被富集，Sec C 处理的细胞中其效应物 S100A8 显著降低，但其在 CSC 干性中的作用尚未完全阐明。我们发现 S100A8 的过表达阻碍了 Sec C 对 CSC 的抑制作用，而 S100A8 的缺乏则减弱了 CSC 的干性特征，从而增强了 Sec C 对它们的杀伤活性。同时，属于 IL17 下游轴的 p38 信号通路也可以介导 CSC 并与 Sec C 对抗。值得注意的是，我们发现 S100A8 的上调增加了 p38 蛋白水平，而 p38 反过来又促进了 S100A8 的表达。这表明 p38 与 S100A8 之间可能存在相互反馈回路。我们的研究发现 Sec C 是一种强大的抗结直肠 CSC 药物，p38-S100A8 正反馈回路介导 Sec C 活性。这表明 Sec C 可能成为结直肠癌治疗中有前途的临床候选药物，而 S100A8 可能是一个有前途的药物靶点。
Zotero 插件
