title: Identification of sennoside A as a novel inhibitor of the slingshot (SSH) family proteins related to cancer metastasis.
abstract: Phospho-cofilin (p-cofilin), which has a phosphate group on Ser-3, is involved in actin polymerization. Its dephosphorylated form promotes filopodia formation and cell migration by enhancing actin depolymerization. Protein phosphatase slingshot homologs (SSHs), known as dual-specificity phosphatases, catalyze hydrolytic removal of the Ser-3 phosphate group from phospho-cofilin. Aberrant SSH activity results in cancer metastasis, implicating SSHs as potential therapeutic targets for cancer metastasis. In this study, we screened 658 natural products purified from traditional oriental medicinal plants to identify three potent SSH inhibitors with submicromolar or single-digit micromolar Kivalues: gossypol, hypericin, and sennoside A. The three compounds were purified from cottonseed, Saint John's wort, and rhubarb, respectively. Sennoside A markedly increased cofilin phosphorylation in pancreatic cancer cells, leading to impaired actin dynamics in pancreatic cancer cells with or without EGF stimulation and reduced motility and invasiveness in vitro and in vivo. Collaboratively, these results demonstrate that sennoside A is a novel inhibitor of SSHs and suggest that it may be valuable in the development of pharmaceutical drugs for treating cancer metastasis.
authors.affiliation: Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Seon Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon 34113, Republic of Korea.
authors.forename: Wooil
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Young Geun
authors.initials: YG
authors.lastname: Lee
authors.affiliation: Research Institute of Biomolecular Chemistry, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon 34113, Republic of Korea. Electronic address: jekmin@kribb.re.kr.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.affiliation: National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28116, Republic of Korea. Electronic address: srlee@kribb.re.kr.
authors.forename: Sang-Rae
authors.initials: SR
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea; Research Institute of Biomolecular Chemistry, Dongguk University, Seoul 100-715, Republic of Korea. Electronic address: sjchung@dongguk.edu.
authors.forename: Sang J
authors.initials: SJ
authors.lastname: Chung
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012676:Senna Extract / Q000494:pharmacology*; D000081226:Sennosides
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D000970:Antineoplastic Agents; D000081226:Sennosides; D012676:Senna Extract; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human
keywords: Cofilin; Dual-specificity phosphatase; Natural product; Pancreatic cancer metastasis; Slingshot homologs (SSHs)