title: Kalopanaxsaponin A inhibits the invasion of human oral squamous cell carcinoma by reducing metalloproteinase-9 mRNA stability and protein trafficking.
abstract: An inability to control cancer cell invasion and metastasis is the leading cause of death in patients with cancer. The present study was performed to determine the anti-invasive effect of Kalopanaxsaponin A (KPS-A) on matrix metalloproteinase-9 (MMP-9)-meidated invasion in phorbol 12-myristate 13-acetate (PMA)-stimulated human oral squamous cell carcinoma (OSCC) cells and a murine xenograft model of human OSCC. KPS-A, isolated from Kalopanax pictus, inhibited PMA-induced proliferation and invasion as well as PMA-induced MMP-9 expression and secretion at non-cytotoxic doses. KPS-A treatment reduced the stability of PMA-induced MMP-9 mRNA and inhibited the PMA-induced cytoplasmic translocation of HuR. In PMA-treated cells, KPS-A treatment resulted in the intracellular accumulation of MMP-9 and suppressed Ras-associated binding 1A (Rab1A) expression. KPS-A treatment suppressed PMA-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 and Akt. Furthermore, the oral administration of KPS-A led to substantial inhibition of tumor growth and the expression of proliferating cell nuclear antigen (PCNA), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), HuR, and Rab1A in the tumor tissues of mice inoculated with YD-10B OSCC cells. Collectively, KPS-A inhibits the invasiveness of oral cancer by reducing HuR-mediated MMP-9 mRNA stability and Rab1A-mediated MMP-9 secretion via ERK1/2 and phosphatidylinositide 3-kinase (PI3K)/Akt. Therefore, KPS-A is a promising anti-invasive agent.
authors.affiliation: Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea. peroxiredoxin@yuhs.ac
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Hwang
authors.forename: Kwang-Kyun
authors.initials: KK
authors.lastname: Park
authors.forename: Won-Yoon
authors.initials: WY
authors.lastname: Chung
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000473:pathology; D009361:Neoplasm Invasiveness; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D012503:Saponins; C460644:kalopanax saponin A; D009828:Oleanolic Acid; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate