title: 3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways.
abstract: Expression of CDC28 protein kinase regulatory subunit 1 (Cks1), an adaptor for cyclin-dependent kinases, is tightly regulated at transcriptional and posttranslational levels. Increased expression of Cks1 has been documented to be attributable to cancer progression, chemoresistance, and chemosensitivity. Here we report that ectopic overexpression of Cks1b in human lung cancer cells (Cks1b-OE) induces chemoresistance of the cells to cisplatin (CDDP) and doxorubicin (DOX) through mechanisms independent of its canonical Skp2-p27 pathway. Further dissection with application of shRNA 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 MEK1/2 rendered a similar magnitude of antitumor activity by resensitization of the chemoresistant Cks1b-OE cells to CDDP and DOX, suggesting that both Hsp90 and MEK1/2 are essential to Cks1b for induction of chemoresistance. Moreover, 3-O-(Z)-coumaroyloleanolic acid (3-COA), an active ingredient of oleanolic acid in the leaves of E. oldhamii Maxim, that has been shown to have antitumor activity against A549 lung cancer cells, mimicked PU-H71, a Hsp90-specific inhibitor, in antitumor activity when used alone or in combination with CDDP or DOX in Cks1b-OE cells and recurrent primary human lung cancer cells both in vitro and in vivo, suggesting that 3-COA is a novel Hsp90 inhibitor. 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.
authors.affiliation: The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China; The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Mingna
authors.initials: M
authors.lastname: Sun
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Guo
authors.affiliation: The College of Pharmaceutics Science, Guangdong Pharmaceutics Science University, Guangzhou, Guangdong 510412, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Gu
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Huaying
authors.initials: H
authors.lastname: Wen
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Siyan
authors.initials: S
authors.lastname: Liao
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
authors.forename: Bohang
authors.initials: B
authors.lastname: Zeng
authors.affiliation: The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510356, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Yueshan
authors.initials: Y
authors.lastname: Li
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Yu
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MA 20814, USA. Electronic address: yh_feng111@163.com.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Feng
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, China. Electronic address: zhouyi0264@gzhmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use; D042846:CDC2-CDC28 Kinases / Q000096:biosynthesis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D047368:Tumor Burden / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; C093090:CKS1B protein, human; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-; D009828:Oleanolic Acid; D042846:CDC2-CDC28 Kinases; D020930:MAP Kinase Kinase Kinases
keywords: 3-COA; Chemoresistance; Cks1b; Hsp90; Lung cancer; MEK1/2