title: Exchange protein directly activated by cyclic AMP increases melanoma cell migration by a Ca2+-dependent mechanism.
abstract: Melanoma has a poor prognosis due to its strong metastatic ability. Although Ca(2+) plays a major role in cell migration, little is known about the role of Ca(2+) in melanoma cell migration. We recently found that the exchange protein directly activated by cyclic AMP (Epac) increases melanoma cell migration via a heparan sulfate-related mechanism. In addition to this mechanism, we also found that Epac regulates melanoma cell migration by a Ca(2+)-dependent mechanism. An Epac agonist increased Ca(2+) in several different melanoma cell lines but not in melanocytes. Ablation of Epac1 with short hairpin RNA inhibited the Epac agonist-induced Ca(2+) elevation, suggesting the critical role of Epac1 in Ca(2+) homeostasis in melanoma cells. Epac-induced Ca(2+) elevation was negated by the inhibition of phospholipase C (PLC) and inositol triphosphate (IP(3)) receptor. Furthermore, Epac-induced cell migration was reduced by the inhibition of PLC or IP(3) receptor. These data suggest that Epac activates Ca(2+) release from the endoplasmic reticulum via the PLC/IP(3) receptor pathway, and this Ca(2+) elevation is involved in Epac-induced cell migration. Actin assembly was increased by Epac-induced Ca(2+), suggesting the involvement of actin in Epac-induced cell migration. In human melanoma specimens, mRNA expression of Epac1 was higher in metastatic melanoma than in primary melanoma, suggesting a role for Epac1 in melanoma metastasis. In conclusion, our findings reveal that Epac is a potential target for the suppression of melanoma cell migration, and, thus, the development of metastasis.
authors.affiliation: Department of Cell Biology and Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Erdene
authors.initials: E
authors.lastname: Baljinnyam
authors.forename: Mariana S
authors.initials: MS
authors.lastname: De Lorenzo
authors.forename: Lai-Hua
authors.initials: LH
authors.lastname: Xie
authors.forename: Mizuka
authors.initials: M
authors.lastname: Iwatsubo
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
authors.forename: James S
authors.initials: JS
authors.lastname: Goydos
authors.forename: Martha C
authors.initials: MC
authors.lastname: Nowycky
authors.forename: Kousaku
authors.initials: K
authors.lastname: Iwatsubo
mesh_terms: D000199:Actins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D012333:RNA, Messenger; D002118:Calcium