cAMP plays a critical role in regulating migration of various
cancers. This role is context dependent and is determined by which of the two main cAMP sensors is at play:
cAMP-dependent protein kinase or exchange
protein directly activated by cAMP (
EPAC). Recently, we have shown that the cAMP sensor
protein EPAC1 promotes invasion/migration of pancreatic ductal
adenocarcinoma (PDA) in vitro. In this study, we investigated the role of EPAC1 in invasion and
metastasis of PDA in vivo, and evaluated the therapeutic potential of
EPAC inhibitors as antimetastasis agents for this
neoplasm. We employed an orthotopic metastatic mouse model in which the PDA cells MIA PaCa-2 were injected into the pancreas of athymic nude mice, and their local and distant spread was monitored by in vivo imaging and histologic evaluation of the number of metastatic foci in the liver. Either genetic suppression of EPAC1 or its pharmacologic inhibition with 3-(5-tert-butyl-
isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-
propionitrile, an
EPAC-specific antagonist recently identified in our laboratory, decreased invasion and
metastasis of the PDA cells. Mechanistically, EPAC1 promotes activation and trafficking of
integrin β1, which plays an essential role in PDA migration and
metastasis. Our data show that EPAC1 facilitates
metastasis of PDA cells and EPAC1 might be a potential novel therapeutic target for developing antimetastasis agents for PDA.