Norcantharidin regulates ERα signaling and tamoxifen resistance via targeting miR-873/CDK3 in breast cancer cells

Xiumei Zhang; Bingfeng Zhang; Panhong Zhang; Lihui Lian; Lianlian Li; Zhihong Qiu; Kai Qian; An Chen; Qiongqing Liu; Yinjie Jiang; Jiajun Cui; Bing Qi

doi:10.1371/journal.pone.0217181

Norcantharidin regulates ERα signaling and tamoxifen resistance via targeting miR-873/CDK3 in breast cancer cells

PLoS One. 2019 May 23;14(5):e0217181. doi: 10.1371/journal.pone.0217181. eCollection 2019.

Authors

Xiumei Zhang^{1

2}, Bingfeng Zhang², Panhong Zhang^{1

2}, Lihui Lian³, Lianlian Li¹, Zhihong Qiu¹, Kai Qian¹, An Chen¹, Qiongqing Liu^{1

2}, Yinjie Jiang¹, Jiajun Cui¹, Bing Qi³

Affiliations

¹ The Center for Translational Medicine, Yichun University, Yichun, Jiangxi, P.R. China.
² College of Chemistry and Bio-engineering, Yichun University, Yichun, Jiangxi, P.R. China.
³ Department of Cell Biology, College of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, P.R. China.

Abstract

MiR-873/CDK3 has been shown to play a critical role in ERα signaling and tamoxifen resistance. Thus, targeting this pathway may be a potential therapeutic approach for the treatment of ER positive breast cancer especially tamoxifen resistant subtype. Here we report that Norcantharidin (NCTD), currently used clinically as an ani-cancer drug in China, regulates miR-873/CDK3 axis in breast cancer cells. NCTD decreases the transcriptional activity of ERα but not ERβ through the modulation of miR-873/CDK3 axis. We also found that NCTD inhibits cell proliferation and tumor growth and miR-873/CDK3 axis mediates cell proliferation suppression of NCTD. More important, we found that NCTD sensitizes resistant cells to tamoxifen. NCTD inhibits tamoxifen induced the transcriptional activity as well ERα downstream gene expressions in tamoxifen resistant breast cancer cells. In addition, we found that NCTD restores tamoxifen induced recruitments of ERα co-repressors N-CoR and SMRT. Knockdown of miR-873 and overexpression of CDK3 diminish the effect of NCTD on tamoxifen resistance. Our data shows that NCTD regulates ERα signaling and tamoxifen resistance by targeting miR-873/CDK3 axis in breast cancer cells. This study may provide an alternative therapy strategy for tamoxifen resistant breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents, Hormonal / pharmacology
Apoptosis
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Cell Proliferation
Cyclin-Dependent Kinase 3 / genetics
Cyclin-Dependent Kinase 3 / metabolism*
Drug Resistance, Neoplasm / drug effects*
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism*
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Nude
MicroRNAs / genetics*
Signal Transduction
Tamoxifen / pharmacology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Antineoplastic Agents, Hormonal
Bridged Bicyclo Compounds, Heterocyclic
ESR1 protein, human
Estrogen Receptor alpha
MIRN873 microRNA, human
MicroRNAs
Tamoxifen
norcantharidin
CDK3 protein, human
Cyclin-Dependent Kinase 3

Grants and funding

This work was supported by University Science & Technology landing project of Jiangxi province (Grant No. 93KJLD12093, CJ) (http://www.jxedu.gov.cn/) and National Natural Science Foundation of China (No. 31660325, CJ) (http://www.nsfc.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.