Cyclic AMP regulates the migration and invasion potential of human pancreatic cancer cells. Mol Carcinog 2015 Mar;54(3):203-15
Date
10/12/2013Pubmed ID
24115212Pubmed Central ID
PMC4087083DOI
10.1002/mc.22091Scopus ID
2-s2.0-84926109550 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
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.
Author List
Zimmerman NP, Roy I, Hauser AD, Wilson JM, Williams CL, Dwinell MBAuthors
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of WisconsinCarol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
1-Methyl-3-isobutylxanthineAmides
Apoptosis
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cell Movement
Cell Proliferation
Colforsin
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Deoxycytidine
Enzyme Inhibitors
Humans
Neoplasm Invasiveness
Pancreatic Neoplasms
Phosphodiesterase Inhibitors
Pyridines
Quinolones
Vasodilator Agents
rho GTP-Binding Proteins
rhoA GTP-Binding Protein
rhoC GTP-Binding Protein
