Abstract
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.
Footnotes
- Received August 4, 2014.
- Accepted November 7, 2014.
M.A. is a recipient of training fellowships from the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia supported by the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM89657-3], and the Biodefense Training Program at the University of Texas Medical Branch supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant T32-AI60549-10]. X.C. is supported by National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM066170 and R01-GM106218]. C.C. is a recipient of the National Cancer Institute Mentored Clinical Scientist Development Award [K08-CA125209]. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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