title: 4-Methylumbelliferone Suppresses Hyaluronan Synthesis and Tumor Progression in SCID Mice Intra-abdominally Inoculated With Pancreatic Cancer Cells.
abstract: Pancreatic ductal adenocarcinoma contains large amounts of the glycosaminoglycan hyaluronan (HA), which is involved in various physiological processes. Here, we aimed to clarify the anticancer mechanisms of 4-methylumbelliferone (MU), a well-known HA synthesis inhibitor.
  
  
  
  MIA PaCa-2 human pancreatic cancer cells were used. We evaluated cellular proliferation, migration, and invasion in the presence of MU, exogenous HA, and an anti-CD44 antibody. We also analyzed apoptosis, CD44 expression, and HA-binding ability using flow cytometry. The HA content in tumor tissue was quantified and histopathologically investigated in mice who had been inoculated with cancer cells.
  
  
  
  In vitro, MU inhibited pericellular HA matrix formation; however, HAS3 mRNA was up-regulated. Treatment with 0.5 mM MU suppressed cellular proliferation by 26.4%, migration by 14.7%, and invasion by 22.7%. Moreover, MU also significantly increased apoptosis. CD44 expression and HA-binding ability were not altered by MU. In vivo, MU suppressed HA accumulation in pancreatic tumors and improved survival times in tumor-bearing mice.
  
  
  
  4-Methylumbelliferone indirectly caused apoptosis in pancreatic cancer cells by inhibiting HA production. 4-Methylumbelliferone may be a promising agent in the treatment of pancreatic cancer.
authors.affiliation: From the Departments of *Gastroenterological Surgery and †Glycotechnology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nagase
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kudo
authors.forename: Akiko
authors.initials: A
authors.lastname: Suto
authors.forename: Eri
authors.initials: E
authors.lastname: Yoshida
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Suto
authors.forename: Mika
authors.initials: M
authors.lastname: Negishi
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kakizaki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hakamada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D000076002:Hyaluronan Synthases / Q000235:genetics / Q000378:metabolism; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006923:Hymecromone / Q000494:pharmacology*; D007202:Indicators and Reagents / Q000494:pharmacology; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D018960:Hyaluronan Receptors; D007202:Indicators and Reagents; D006923:Hymecromone; D006820:Hyaluronic Acid; D000076002:Hyaluronan Synthases