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鱼藤酮通过ROS/Ca/AMPK途径调节ZO-2的表达和定位，从而抑制骨肉瘤转移。

Rotenone inhibited osteosarcoma metastasis by modulating ZO-2 expression and location via the ROS/Ca/AMPK pathway.

作者信息

Ma Xiang, Li Zhen, Ma Hengwei, Jiang Kun, Chen Bao, Wang Weiquan, Zhu Ziqiang, Wang Jianqiang, Yang Zuozhang, Yunqing Wang, Dong Suwei

机构信息

Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.

Department of Medical Oncology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China.

出版信息

Redox Rep. 2025 Dec;30(1):2493556. doi: 10.1080/13510002.2025.2493556. Epub 2025 Apr 17.

DOI:10.1080/13510002.2025.2493556
PMID:40247635
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12010658/
Abstract

BACKGROUND

Pulmonary metastases in osteosarcoma (OS) are associated with a poor prognosis. Rotenone has shown anti-cancer activity. However, its effects on metastasis and the underlying mechanisms remain unknown. This study investigated the potential use of Rotenone for OS treatment.

METHODS

The effect of Rotenone and ROS/Ca/AMPK/ZO-2 pathway on metastasis and EMT was evaluated by Western blot, Transwell and Wound healing. Flow cytometer was employed to measure the intracellular Ros and Ca levels. The subcellular location of ZO-2 was detected by IF, interaction between AMPK and ZO-2 were examined by Co-IP. Then, subcutaneous tumor and metastasis models were used to evaluate the function of Rotenone in OS metastasis.

RESULTS

Rotenone-induced ROS led to increased intracellular Ca, which promoted the EMT of OS cells through activation of AMPK and ZO-2 nuclear translocation. Inhibition of ROS production decreased intracellular Ca, restraining AMPK activity. Knock-down of ZO-2 significantly suppressed the anti-metastasis effects of Rotenone in OS cells. Moreover, Rotenone elevated p-AMPK and ZO-2 expression but inhibited EMT and lung metastasis in . These results provide evidence supporting an anti-metastatic effect of Rotenone. These findings support the use of Rotenone in the prevention of OS metastasis.

摘要

背景

骨肉瘤（OS）的肺转移与预后不良相关。鱼藤酮已显示出抗癌活性。然而，其对转移的影响及潜在机制仍不清楚。本研究调查了鱼藤酮在骨肉瘤治疗中的潜在用途。

方法

通过蛋白质免疫印迹法、Transwell小室法和伤口愈合实验评估鱼藤酮以及ROS/Ca/AMPK/ZO-2信号通路对转移和上皮-间质转化（EMT）的影响。采用流式细胞仪测量细胞内ROS和Ca水平。通过免疫荧光法检测ZO-2的亚细胞定位，通过免疫共沉淀法检测AMPK与ZO-2之间的相互作用。然后，利用皮下肿瘤和转移模型评估鱼藤酮在骨肉瘤转移中的作用。

结果

鱼藤酮诱导产生的ROS导致细胞内Ca增加，通过激活AMPK和ZO-2核转位促进骨肉瘤细胞的EMT。抑制ROS生成可降低细胞内Ca，抑制AMPK活性。敲低ZO-2可显著抑制鱼藤酮对骨肉瘤细胞的抗转移作用。此外，鱼藤酮可提高p-AMPK和ZO-2的表达，但抑制骨肉瘤细胞的EMT和肺转移。这些结果为鱼藤酮的抗转移作用提供了证据支持。这些发现支持将鱼藤酮用于预防骨肉瘤转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/6a6dae86a7ad/YRER_A_2493556_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/d194fcc4e5e8/YRER_A_2493556_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/2710161e5b10/YRER_A_2493556_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/9b66cf3b6558/YRER_A_2493556_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/62e1a20d8857/YRER_A_2493556_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/6a6dae86a7ad/YRER_A_2493556_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/d194fcc4e5e8/YRER_A_2493556_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/2710161e5b10/YRER_A_2493556_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/9b66cf3b6558/YRER_A_2493556_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/62e1a20d8857/YRER_A_2493556_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fda7/12010658/6a6dae86a7ad/YRER_A_2493556_F0005_OC.jpg

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