A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion.
Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer.
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0615, USA. xcheng@utmb.edu
Muayad
M
Almahariq
Tamara
T
Tsalkova
Fang C
FC
Mei
Haijun
H
Chen
Jia
J
Zhou
Sarita K
SK
Sastry
Frank
F
Schwede
Xiaodong
X
Cheng
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D000242:Cyclic AMP / Q000737:chemistry; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
C579558:3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile; D000970:Antineoplastic Agents; D020662:Guanine Nucleotide Exchange Factors; D006835:Hydrazones; D007328:Insulin; D007555:Isoxazoles; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D020827:rap1 GTP-Binding Proteins