Am J Physiol Cell Physiol AJP: Regulatory, Integrative and Comparative Physiology
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Am J Physiol Cell Physiol 297: C802-C813, 2009. First published August 5, 2009; doi:10.1152/ajpcell.00129.2009
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RECEPTORS AND SIGNAL TRANSDUCTION

Epac increases melanoma cell migration by a heparan sulfate-related mechanism

Erdene Baljinnyam,1,* Kousaku Iwatsubo,1,* Reiko Kurotani,3 Xu Wang,1 Coskun Ulucan,1 Mizuka Iwatsubo,1 David Lagunoff,1 and Yoshihiro Ishikawa1,2,3

1Department of Cell Biology and Molecular Medicine, and 2Department of Medicine (Cardiology), New Jersey Medical School-University of Medicine and Dentistry of New Jersey, Newark, New Jersey; 3Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Submitted 23 March 2009 ; accepted in final form 3 August 2009

Melanoma, the most malignant form of human skin cancer, has a poor prognosis due to its strong metastatic ability. It was recently demonstrated that Epac, an effector molecule of cAMP, is involved in regulating cell migration; however, the role of Epac in melanoma cell migration remains unclear. We thus examined whether Epac regulates cell migration and metastasis of melanoma. Epac activation, by either specific agonist or overexpression of Epac, increased melanoma cell migration. Deletion of endogenous Epac with small interfering RNA decreased basal melanoma cell migration. These data suggested a major role of Epac in melanoma cell migration. Epac-induced cell migration was mediated by translocation of syndecan-2, a cell-surface heparan sulfate proteoglycan, to lipid rafts. This syndecan-2 translocation was regulated by tubulin polymerization via the Epac/phosphoinositol-3 kinase pathway. Epac-induced cell migration was also regulated by the production of heparan sulfate, a major extracellular matrix. Epac-induced heparan sulfate production was attributable to the increased expression of N-deacetylase/N-sulfotransferase-1 (NDST-1) accompanied by an increased NDST-1 translation rate. Finally, Epac overexpression enhanced lung colonization of melanoma cells in mice. Taken together, these data indicate that Epac regulates melanoma cell migration/metastasis mostly via syndecan-2 translocation and heparan sulfate production.

metastasis; phosphoinositol-3 kinase; N-deacetylase/N-sulfotransferase-1


Address for reprint requests and other correspondence: K. Iwatsubo, G-653, MSB, 185 S. Orange Ave., Newark, NJ 07103 (E-mail: iwatsuko{at}umdnj.edu) or Y. Ishikawa, 3-9 Fukuura Kanazawa-ku, Yokohama, 236-0004, Japan.




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Epac in melanoma: a contributor to tumor cell physiology? Focus on "Epac increases melanoma cell migration by a heparin sulfate-related mechanism"
Am J Physiol Cell Physiol, October 1, 2009; 297(4): C797 - C799.
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