Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells.
10.1016/j.apsb.2019.03.001
- Author:
Linlin CHANG
1
;
Yan HU
1
;
Yingying FU
1
;
Tianyi ZHOU
1
;
Jun YOU
2
;
Jiamin DU
1
;
Lin ZHENG
1
;
Ji CAO
1
;
Meidan YING
1
;
Xiaoyang DAI
1
;
Dan SU
2
;
Qiaojun HE
1
;
Hong ZHU
1
;
Bo YANG
1
Author Information
1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
2. Zhejiang Cancer Hospital, Hangzhou 310022, China.
- Publication Type:Journal Article
- Keywords:
CO2, carbon dioxide;
DMEM, Dulbecco׳s modified Eagle׳s medium;
Drug resistance;
EGFR, epidermal growth factor receptor;
ELISA, enzyme-linked immunosorbent assay;
EMT, epithelial-mesenchymal transition;
FBS, fetal bovine serum;
HGF, hepatocyte growth factor;
IHC, immunohistochemistry;
ITGA5, integrin subunit alpha 5;
OS, overall survival;
Ovarian cancer;
PBS, phosphate buffered solution;
PFS, progression-free survival;
PPS, postprogression survival;
PVDF, polyvinylidene fluoride;
SDS, sodium dodecyl sulfate;
Slug;
TGF-β, transforming growth factor-beta;
VEGFR, kinase insert domain receptor;
XL184;
c-Met;
cDNA, complementary DNA;
qRT-PCR, quantitative reverse transcription polymerase chain reaction
- From:
Acta Pharmaceutica Sinica B
2019;9(3):484-495
- CountryChina
- Language:English
-
Abstract:
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 metastatic-associated 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 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 and . 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.
