The hyaluronan synthesis inhibitor 4-methylumbelliferone exhibits antitumor effects against mesenchymal‑like canine mammary tumor cells

Saito,Teruyoshi; Dai,Tamura; Asano,Ryuji

doi:10.3892/ol.2013.1124

The hyaluronan synthesis inhibitor 4-methylumbelliferone exhibits antitumor effects against mesenchymal‑like canine mammary tumor cells

Authors:
- Teruyoshi Saito
- Tamura Dai
- Ryuji Asano
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Affiliations: Laboratory of Veterinary Pharmacology, Nihon University College of Bioresource Science, Fujisawa, Kanagawa 252-0880, Japan
Published online on: January 10, 2013 https://doi.org/10.3892/ol.2013.1124
Pages: 1068-1074

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Abstract

Hyaluronan (HA), a principal constituent of the extracellular matrix (ECM), mediates growth and metastasis of tumor cells. The role of HA in the epithelial-mesenchymal transition (EMT) is well known, and increased ECM remodeling is observed in mesenchymal-like cells. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) is anti-tumorigenic for various malignant tumors. However, the antitumor effect of 4-MU against canine mammary tumor cells that possess a mesenchymal-like phenotype is unclear. We examined the antitumor effect of 4-MU on CF41.Mg mesenchymal-like canine mammary tumor cells. We investigated the influence of 4-MU on the expression of HA synthase (HAS) 1-3 mRNA and observed dose-dependent downregulation of HAS2 mRNA at 24-72 h; in contrast, HAS3 expression was elevated at 24 h. Thus, 4-MU inhibited HA synthesis via HAS2 repression. 4-MU also inhibited cell proliferation and induced apoptosis in the CF41.Mg cells. Our experiments showed that 4-MU-induced apoptosis in CF41.Mg cells involved induction of the pro-apoptotic gene BAX. We also assessed motility and found that 4-MU reduced chemokinesis and chemotaxis in CF41.Mg cells. Our data suggest that 4-MU may serve as a candidate therapeutic agent for the treatment of canine mammary tumors. Since 4-MU exhibits antitumor activity in mesenchymal-like cells, it may also be a useful inhibitor of canine mammary tumor invasion and metastasis.

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