Overexpression of exchange protein directly activated by cAMP-1 (EPAC1) attenuates bladder cancer cell migration

Hirona Ichikawa; Momoe Itsumi; Shunichi Kajioka; Tomoko Maki; Ken Lee; Makoto Tomita; Shoji Yamaoka

doi:10.1016/j.bbrc.2017.10.142

Overexpression of exchange protein directly activated by cAMP-1 (EPAC1) attenuates bladder cancer cell migration

Biochem Biophys Res Commun. 2018 Jan 1;495(1):64-70. doi: 10.1016/j.bbrc.2017.10.142. Epub 2017 Oct 28.

Authors

Hirona Ichikawa¹, Momoe Itsumi², Shunichi Kajioka³, Tomoko Maki⁴, Ken Lee⁴, Makoto Tomita⁵, Shoji Yamaoka⁶

Affiliations

¹ Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
² Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Applied Urology and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: momomolv@tmd.ac.jp.
³ Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Applied Urology and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kajioka@uro.med.kyushu-u.ac.jp.
⁴ Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Applied Urology and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁵ Clinical Research Center, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan.
⁶ Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: shojmmb@tmd.ac.jp.

PMID: 29111327
DOI: 10.1016/j.bbrc.2017.10.142

Abstract

Exchange protein directly activated by cAMP (EPAC) is a mediator of a cAMP signaling pathway that is independent of protein kinase A. EPAC has two isoforms (EPAC1 and EPAC2) and is a cAMP-dependent guanine nucleotide exchange factor for the small GTPases, Rap1 and Rap2. Recent studies suggest that EPAC1 has both positive and negative influences on cancer and is involved in cell proliferation, apoptosis, migration and metastasis. We report that EPAC1 and EPAC2 expression levels were significantly lower in bladder cancer tissue than in normal bladder tissue. In addition, bladder cancer cell lines showed reduced EPAC1 mRNA expression. Furthermore, EPAC1 overexpression in bladder cancer cell lines induced morphologic changes and markedly suppressed cell migration without affecting cell viability. The overexpressed EPAC1 preferentially localized at cell-cell interfaces. In conclusion, reduced EPAC1 expression in bladder tumors and poor migration of EPAC1-overexpressing cells implicate EPAC1 as an inhibitor of bladder cancer cell migration.

Keywords: Bladder cancer; Cell migration; EPAC.

MeSH terms

Carcinoma, Transitional Cell / genetics
Carcinoma, Transitional Cell / metabolism*
Carcinoma, Transitional Cell / pathology*
Cell Line, Tumor
Cell Movement / genetics
Cell Movement / physiology
Female
Gene Expression
Guanine Nucleotide Exchange Factors / genetics
Guanine Nucleotide Exchange Factors / metabolism*
Humans
Male
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism
Shelterin Complex
Telomere-Binding Proteins / metabolism
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism*
Urinary Bladder Neoplasms / pathology*

Substances

Guanine Nucleotide Exchange Factors
RAPGEF3 protein, human
RAPGEF4 protein, human
RNA, Messenger
RNA, Neoplasm
Shelterin Complex
TERF2IP protein, human
Telomere-Binding Proteins