title: Cyclic AMP regulates the migration and invasion potential of human pancreatic cancer cells.
abstract: Aggressive dissemination and metastasis of pancreatic ductal adenocarcinoma (PDAC) results in poor prognosis and marked lethality. Rho monomeric G protein levels are increased in pancreatic cancer tissue. As the mechanisms underlying PDAC malignancy are little understood, we investigated the role for cAMP in regulating monomeric G protein regulated invasion and migration of pancreatic cancer cells. Treatment of PDAC cells with cAMP elevating agents that activate adenylyl cyclases, forskolin, protein kinase A (PKA), 6-Bnz-cAMP, or the cyclic nucleotide phosphodiesterase inhibitor cilostamide significantly decreased migration and Matrigel invasion of PDAC cell lines. Inhibition was dose-dependent and not significantly different between forskolin or cilostamide treatment. cAMP elevating drugs not only blocked basal migration, but similarly abrogated transforming-growth factor-β-directed PDAC cell migration and invasion. The inhibitory effects of cAMP were prevented by the pharmacological blockade of PKA. Drugs that increase cellular cAMP levels decreased levels of active RhoA or RhoC, with a concomitant increase in phosphorylated RhoA. Diminished Rho signaling was correlated with the appearance of thickened cortical actin bands along the perimeter of non-motile forskolin or cilostamide-treated cells. Decreased migration did not reflect alterations in cell growth or programmed cell death. Collectively these data support the notion that increased levels of cAMP specifically hinder PDAC cell motility through F-actin remodeling.
authors.affiliation: Department of Microbiology and Molecular Genetics, The Medical College of Wisconsin Cancer Center, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226.
authors.forename: Noah P
authors.initials: NP
authors.lastname: Zimmerman
authors.forename: Ishan
authors.initials: I
authors.lastname: Roy
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hauser
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein; D000093542:Gemcitabine
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D015363:Quinolones; D014665:Vasodilator Agents; D003841:Deoxycytidine; C108830:Y 27632; D005576:Colforsin; C021294:cilostamide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein; D015056:1-Methyl-3-isobutylxanthine; D000093542:Gemcitabine
keywords: Rho; carcinoma metastasis; pancreas; phosphodiesterase; protein kinase A