Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA.

Meng Shen,Dao-Ming Li,Meng-Yao Wu,Long-Pei Chen,Min Tao,Wei Li,Qiaoming Zhi,Fei-Ran Gong,Yadi Wu,Kai Chen

doi:10.1038/srep11836

Abstract

Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in cell cycle control, apoptosis, and cell-fate determination. In the present study, we found that cantharidin repressed the invasive ability of pancreatic cancer cells and downregulated matrix metalloproteinase 2 (MMP2) expression through multiple pathways, including ERK, JNK, PKC, NF-κB, and β-catenin. Interestingly, transcriptional activity of the MMP2 promoter increased after treatment with PP2A inhibitors, suggesting the involvement of a posttranscriptional mechanism. By using an mRNA stability assay, we found accelerated degradation of MMP2 mRNA after treatment of cantharidin. Microarray analyses revealed that multiple genes involved in the 3'→5' decay pathway were upregulated, especially genes participating in cytoplasmic deadenylation. The elevation of these genes were further demonstrated to be executed through ERK, JNK, PKC, NF-κB, and β-catenin pathways. Knockdown of PARN, RHAU, and CNOT7, three critical members involved in cytoplasmic deadenylation, attenuated the downregulation of MMP2. Hence, we present the mechanism of repressed invasion by cantharidin and other PP2A inhibitors through increased degradation of MMP2 mRNA by elevated cytoplasmic deadenylation.

Highlights

Cantharidin could repress the invasion of bladder carcinoma cells through the downregulation of matrix metalloproteinase 2 (MMP2)[7], the main proteinase that participates in the degradation of cellular matrix
In vitro studies have demonstrated that proteolytic degradation of extracellular matrix (ECM) components is a major step in pancreatic cancer invasion[15,16]
MMPs are a family of ECM modifying enzymes associated with tumour progression and metastasis by degradation of all components of the ECM

Summary

Introduction

Cantharidin could repress the invasion of bladder carcinoma cells through the downregulation of matrix metalloproteinase 2 (MMP2)[7], the main proteinase that participates in the degradation of cellular matrix. The detailed mechanism involved still requires full exploration. We investigated whether cantharidin could repress the invasive ability of pancreatic cancer cells through downregulation of MMP2. Cantharidin is a selective inhibitor of serine/threonine protein phosphatase 2A (PP2A). We observed that inhibition of PP2A in pancreatic cancer cells resulted in phosphorylation of multiple substrates, including extracellular signal-related kinase (ERK), JNK, Iκ B kinase (IKK), protein kinase C (PKC), and β -catenin. We looked to determine if these pathways were involved in the regulation of invasion and MMP2 expression by cantharidin in pancreatic cancer cells

Methods

Results

Conclusion