3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways

被引：0

作者：

WANG He ^{[1
,2
]}

GUO Jia-yi ^{[1
]}

MA Lei ^{[3
]}

DENG Sai ^{[1
]}

LIAO Si-yan ^{[1
]}

SUN Ming-na ^{[1
]}

DU Ling-ran ^{[1
]}

PENG Wei ^{[1
]}

WEI Min-yan ^{[3
]}

LIU Bin ^{[3
]}

CHEN Jing-qi ^{[1
]}

ZENG Bo-hang ^{[2
]}

LI Yue-shan ^{[1
]}

YU Xi-yong ^{[1
]}

FENG Ying-hong ^{[1
,4
]}

YI Zhou ^{[1
]}

机构：

[1] The College of Pharmaceutics Science,Guangzhou Medical University

[2] The Second Affiliated Hospital,Guangzhou Medical University

[3] The College of Pharmaceutics Science, Guangdong Pharmaceutics Science University

[4] Department of Pharmacology & Molecular Therapeutics,Uniformed Services University of the Health Sciences

来源：

中国药理学与毒理学杂志 | 2016年 / 10期

基金：

中国国家自然科学基金;

关键词：

Cks1b; Hsp90; MEK1/2; lung cancer; 3-COA; chemoresistance;

D O I：

暂无

中图分类号：

R285.5 [中药实验药理];

学科分类号：

1008 ;

摘要：

OBJECTIVE To investigate 3-O-(Z)-coumaroyloleanolic acid(3-COA),an active ingredient of oleanolic acid in the TAIWANG leaves of E.oldhamii Maxim,that has been shown to have antitumor activity against A549 lung cancer cells,overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways.METHODS Cisplatin(CDDP)and doxorubicin(DOX)sensitivity was assessed through proliferation,viability,and clonogenic potential induction in cells overexpressing Cks1b(Cks1b-OE).The mechanism for resistance and 3-COA sensitivity were elucidated by immunoblot analysis of Hsp90 and MEK,and confirmed by sh RNA knockdown.Inhibition of 3-COA or3-COA combined with CDDP(3-COA&CDDP)was assayed in early primary lung cancer(IPH),late primary lung cancer(RFH)cells,and tumor-burdened immunodeficiency mice in vivo.RESULTS The ectopic overexpression of Cks1b in human lung cancer cells induces chemoresistance of the cells to CDDP and DOX,but not3-COA,through mechanisms independent of its canonical Skp2-p27 pathway.Further dissection with application of shR NA and selective inhibitors reveals that Hsp90 and MEK1/2 are the critical components of the non-canonical pathways responsible for the Cks1b-induced chemoresistance.Interestingly,inhibition of either Hsp90 or MEK1/2rendered a similar magnitude of antitumor activity by resensitization of the chemoresistant Cks1b-OE cells to CDDP and DOX,suggesting that both Hsp90 and MEK1/2are essentialto Cks1b for induction of chemoresistance.IC50of 3-COA is 6.82μmol·L-1in H358 Cks1b and8.22μmol·L-1in H226 Cks1b,which were not significantly higher than those in H358 EV and H226 EV,respectively.Furthermore,3-COA mimicked PU-H71,a Hsp90-specific inhibitor,targeted Hsp90 and MEK to reduce the expression of their downstream,respectively.Importantly,compared with CDDP treatment,3-COA or 3-COA&CDDP signifi-cantly inhibited RFH cells in vitro.Moreover,3-COA or3-COA&CDDP significantly prolonged more survival for a H358 Cks1b-OE inducing tumor-burdened mice than PD98059(a MEK-specific inhibitor)in vivo.CONCLUSION Our data report for the first time that Cks1b employs Hsp90 and MEK1/2 pathways in lung cancer cells to develop chemoresistance and identify 3-COA as a potential antitumor drug for clinical treatment of chemoresistant lung cancer.

引用

页码：1078 / 1078

页数：1