title: Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA.
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.
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Meng-Yao
authors.initials: MY
authors.lastname: Wu
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Long-Pei
authors.initials: LP
authors.lastname: Chen
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Zhi
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Fei-Ran
authors.initials: FR
authors.lastname: Gong
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Dao-Ming
authors.initials: DM
authors.lastname: Li
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Yadi
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 1] Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China [2] Jiangsu Institute of Clinical Immunology, Suzhou 215006, China [3] Institute of Medical Biotechnology, Soochow University, Suzhou 215021, China [4] PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou 215021, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tao
authors.affiliation: 1] Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China [2] PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou 215021, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002193:Cantharidin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004794:Enzyme Repression / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D002193:Cantharidin