Tubeimoside-I sensitizes colorectal cancer cells to chemotherapy by inducing ROS-mediated impaired autophagolysosomes accumulation
Tubeimoside-I sensitizes colorectal cancer cells to chemotherapy by inducing ROS-mediated impaired autophagolysosomes accumulation
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Tubeimoside-I 通过诱导 ROS 介导的受损自噬溶酶体积累使结直肠癌细胞对化疗敏感
DOI：
10.1186/s13046-019-1355-0
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发表时间：
2019-08
影响因子：
11.3
通讯作者：
Lei Yunlong
中科院分区：
文献类型：
--
作者：
Yan Jianghong;Dou Xiaoyun;Zhou Jing;Xiong Yuanfeng;Mo Ling;Li Longhao;Lei Yunlong
tubeimoside - i （TBM）是一种植物源性生物活性化合物，在不同肿瘤中均表现出抗肿瘤活性，可增强化疗药物的疗效。然而，其背后的详细机制仍有待阐明。方法采用CCK8法、集落形成法、LDH释放法、流式细胞术和Western blot检测TBM对结直肠癌细胞的毒力。测定对照组和tbm处理的结直肠癌细胞的ROS水平、自噬、凋亡、对5-FU或DOX的化学敏感性等。结果本研究发现TBM能抑制结直肠癌（CRC）细胞的增殖和诱导细胞凋亡。有趣的是，TBM处理既可以通过ros诱导的AMPK激活促进自噬启动，也可以通过抑制溶酶体水解酶来阻断自噬通量，从而导致自噬溶酶体积累大量受损。自噬起始抑制剂（3-MA或选择性消融自噬相关蛋白）可减轻tbm诱导的结直肠癌抑制，而联合使用自噬通量抑制剂氯喹（CQ）可轻微增加tbm诱导的细胞死亡，提示自噬溶酶体积累受损有助于tbm诱导的结直肠癌细胞生长抑制。值得注意的是，作为一种自噬通量抑制剂，TBM可与5-氟尿嘧啶（5-FU）或阿霉素（DOX）协同抑制结直肠癌。结论本研究为TBM对结直肠癌的抗肿瘤活性提供了新的认识，并为TBM在结直肠癌联合治疗中的潜在应用奠定了基础。
BackgroundTubeimoside-I (TBM), a plant-derived bioactive compound, shows antitumor activity in different tumors and can enhance the efficacy of chemotherapeutic agents. However, the detail mechanism underlying remains to be elucidated.MethodsThe cytotoxic potential of TBM towards CRC cells was examined by CCK8 assay, colony formation, LDH release assay, flow cytometry method and Western blots. The ROS levels, autophagy, apoptosis, chemosensitivity to 5-FU or DOX, etc. were determined between control and TBM-treated CRC cells.ResultsIn this study, we found that TBM could inhibit proliferation and induce apoptosis in colorectal cancer (CRC) cells. Intriguingly, TBM treatment could either promote autophagy initiation by ROS-induced AMPK activation, or block autophagy flux through inhibiting lysosomal hydrolytic enzymes, which leaded to massive impaired autophagylysosomes accumulation. Administration of autophagy initiation inhibitor (3-MA or selective ablation of autophagy related proteins) relieves TBM-induced CRC suppression, while combination use of autophagy flux inhibitor chloroquine (CQ) slightly augments TBM-induced cell death, suggesting that impaired autophagylysosomes accumulation contributes to TBM-induced growth inhibition in CRC cells. Notably, as an autophagy flux inhibitor, TBM works synergistically with 5-fluorouracil (5-FU) or doxorubicin (DOX) in CRC suppression.ConclusionTogether, our study provides new insights regarding the anti-tumor activity of TBM against CRC, and established potential applications of TBM for CRC combination therapies in clinic.
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影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1016/b978-1-4160-3251-9.50008-x
发表时间：
2019-10
期刊：
The Lancet
影响因子：
--
作者：
E. Dekker;P. Tanis;J. Vleugels;P. Kasi;M. Wallace
通讯作者：
E. Dekker;P. Tanis;J. Vleugels;P. Kasi;M. Wallace
影响因子：
168.9
作者：
Cunningham, David;Atkin, Wendy;Starling, Naureen
通讯作者：
Starling, Naureen
影响因子：
168.9
作者：
Midgley, R;Kerr, D
通讯作者：
Kerr, D
影响因子：
8.4
作者：
Li, Jie;Hou, Ni;Kuwano, Hiroyuki
通讯作者：
Kuwano, Hiroyuki