Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo.
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.
Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas (M.A., F.C.M., X.C.); and Departments of Pharmacology and Toxicology (M.A.), Surgery (M.R.H., C.C.), and Ophthalmology and Visual Sciences (I.P., M.M.), University of Texas Medical Branch, Galveston, Texas.
Muayad
M
Almahariq
Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas (M.A., F.C.M., X.C.); and Departments of Pharmacology and Toxicology (M.A.), Surgery (M.R.H., C.C.), and Ophthalmology and Visual Sciences (I.P., M.M.), University of Texas Medical Branch, Galveston, Texas.
Celia
C
Chao
Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas (M.A., F.C.M., X.C.); and Departments of Pharmacology and Toxicology (M.A.), Surgery (M.R.H., C.C.), and Ophthalmology and Visual Sciences (I.P., M.M.), University of Texas Medical Branch, Galveston, Texas.
Fang C
FC
Mei
Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas (M.A., F.C.M., X.C.); and Departments of Pharmacology and Toxicology (M.A.), Surgery (M.R.H., C.C.), and Ophthalmology and Visual Sciences (I.P., M.M.), University of Texas Medical Branch, Galveston, Texas.
Mark R
MR
Hellmich
Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas (M.A., F.C.M., X.C.); and Departments of Pharmacology and Toxicology (M.A.), Surgery (M.R.H., C.C.), and Ophthalmology and Visual Sciences (I.P., M.M.), University of Texas Medical Branch, Galveston, Texas.
Igor
I
Patrikeev
Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas (M.A., F.C.M., X.C.); and Departments of Pharmacology and Toxicology (M.A.), Surgery (M.R.H., C.C.), and Ophthalmology and Visual Sciences (I.P., M.M.), University of Texas Medical Branch, Galveston, Texas.
Massoud
M
Motamedi
Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas (M.A., F.C.M., X.C.); and Departments of Pharmacology and Toxicology (M.A.), Surgery (M.R.H., C.C.), and Ophthalmology and Visual Sciences (I.P., M.M.), University of Texas Medical Branch, Galveston, Texas Xiaodong.cheng@uth.tmc.edu.
Xiaodong
X
Cheng
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology
C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D010880:Piperidines; C069701:NPC 15437