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: He Wang, Mingna Sun, Jiayi Guo, Lei Ma, Hui Jiang, Liang Gu, Huaying Wen, Siyan Liao, Jingqi Chen, Bohang Zeng, Yongmei Li, Yueshan Li, Xiyong Yu, Yinghong Feng, Yi Zhou
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 135 Pg. 35-49 (07 01 2017) ISSN: 1873-2968 [Electronic] England
• PMID: 28288818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzodioxoles
• CKS1B protein, human
• HSP90 Heat-Shock Proteins
• Purines
• 9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-
• Oleanolic Acid
• CDC2-CDC28 Kinases
• MAP Kinase Kinase Kinases

Topics

• Adult
• Aged
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzodioxoles (pharmacology, therapeutic use)
• CDC2-CDC28 Kinases (biosynthesis)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects, physiology)
• Female
• Follow-Up Studies
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System (drug effects, physiology)
• Male
• Mice
• Mice, Nude
• Middle Aged
• Oleanolic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Purines (pharmacology, therapeutic use)
• Retrospective Studies
• Tumor Burden (drug effects, physiology)
• Tumor Cells, Cultured