Original articles
Linlin Chang, Yan Hu, Yingying Fu, Tianyi Zhou, Jun You, Jiamin Du, Lin Zheng, Ji Cao, Meidan Ying, Xiaoyang Dai, Dan Su, Qiaojun He, Hong Zhu, Bo Yang. Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 484-495

Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells
Linlin Changa, Yan Hua, Yingying Fua, Tianyi Zhoua, Jun Youb, Jiamin Dua, Lin Zhenga, Ji Caoa, Meidan Yinga, Xiaoyang Daia, Dan Sub, Qiaojun Hea, Hong Zhua, Bo Yanga
a Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;
b Zhejiang Cancer Hospital, Hangzhou 310022, China
Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastaticassociated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.
Key words:    Slug    c-Met    Drug resistance    Ovarian cancer    XL184   
Received: 2019-01-03     Revised:
DOI: 10.1016/j.apsb.2019.03.001
Funds: This work was supported by the National Natural Science Foundation for Distinguished Young Scholar of China (81625024 and 91529304, to Bo Yang), and National Natural Science Foundation of China (81673458, to Hong Zhu; 81503095, to Xiaoyang Dai), Zhejiang Provincial Natural Science Foundation (LY16H310004, to Xiaoyang Dai; China).
Corresponding author: Hong Zhu, Bo Yang     Email:hongzhu@zju.edu.cn;yang924@zju.edu.cn
Author description:
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Linlin Chang
Yan Hu
Yingying Fu
Tianyi Zhou
Jun You
Jiamin Du
Lin Zheng
Ji Cao
Meidan Ying
Xiaoyang Dai
Dan Su
Qiaojun He
Hong Zhu
Bo Yang

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