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-I B, 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'a †'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-I B, 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.
|State||Published - Jul 2 2015|
Bibliographical noteFunding Information:
We thank Prof. Yi Sun (Department of Molecular Biology, Parke-Davis Pharmaceutical Research) for kindly providing pGL2-MMP2 plasmid. This study was supported by the National Natural Science Foundation of China (grant nos 81472296, 81101867, 81272542, 81200369, 81372443 and 81402477), the CSPAC-Celgene Foundation, the China International Medical Foundation (grant no. CIMF-F-H001-057), the Special Foundation of Clinical Medicine of Jiangsu Provincial Bureau of Science and Technology (grant no. BL2014039), the Scientific Research Project of Jiangsu Provincial Bureau of Traditional Chinese Medicine (grant no. L213236), the Medical Scientific Research Project of Jiangsu Provincial Bureau of Health (grant no. Z201206), the Special Foundation of Wu Jieping Medical Foundation for Clinical Scientific Research (grant nos 320.6753.1225 and 320.6750.12242), the Science and Education for Health Foundation of Suzhou for Youth (grant nos SWKQ1003 and SWKQ1011), the Science and Technology Project Foundation of Suzhou (grant nos SYSD2012137 and SYS201335), the Science and Technology Foundation of Suzhou Xiangcheng (grant nos SZXC2012-70 and XJ201451) and a Project Founded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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