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Exchange Protein Directly Activated by cAMP (EPAC1) Promotes Pancreatic Cancer Metastasis
Author(s) -
Mei Fang,
Almahariq Muayad,
Chao Celia,
Hellmich Mark,
Cheng Xiaodong
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.945.3
Subject(s) - metastasis , in vivo , cancer research , pancreatic cancer , context (archaeology) , in vitro , cell migration , pancreas , chemistry , cancer , medicine , biology , biochemistry , paleontology , microbiology and biotechnology
Cyclic adenosine monophosphate (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: PKA or EPAC. Recently, we have shown that the cAMP sensor protein EPAC1 promotes invasion/migration of pancreatic ductal adenocarcinoma (PDA) in vitro . Here we investigated the role of EPAC1 in invasion and metastasis of PDA in vivo , and evaluated the therapeutic potential of EPAC inhibitors as anti‐metastasis 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 histological evaluation of the number of metastatic foci in the liver. Either genetic suppression of EPAC1 or its pharmacologic inhibition with ESI‐09, an EPAC‐specific antagonist recently identified in our lab, 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 shows that EPAC1 facilitates metastasis of PDA cells and EPAC1 might be a potential novel therapeutic target for developing anti‐metastasis agents for PDA.