Exchange Protein Directly Activated by Cyclic AMP Increases Melanoma Cell Migration by a Ca2+-Dependent Mechanism

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-07, Vol.70 (13), p.5607-5617
• Main Authors: BALJINNYAM, Erdene, DE LORENZO, Mariana S, XIE, Lai-Hua, IWATSUBO, Mizuka, CHEN, Suzie, GOYDOS, James S, NOWYCKY, Martha C, IWATSUBO, Kousaku
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Antineoplastic agents; Biological and medical sciences; Calcium - metabolism; Cell Line, Tumor; Cell Movement - physiology; Dermatology; Endoplasmic Reticulum - metabolism; Guanine Nucleotide Exchange Factors - biosynthesis; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Humans; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Inositol Phosphates - metabolism; Medical sciences; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Pharmacology. Drug treatments; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0056

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.