title: Adenylyl cyclase 3/adenylyl cyclase-associated protein 1 (CAP1) complex mediates the anti-migratory effect of forskolin in pancreatic cancer cells.
abstract: Pancreatic cancer is one of the most lethal human malignancies. A better understanding of the intracellular mechanism of migration and invasion is urgently needed to develop treatment that will suppress metastases and improve overall survival. Cyclic adenosine monophosphate (cyclic AMP) is a second messenger that has shown to regulate migration and invasion of pancreatic cancer cells. The rise of cyclic AMP suppressed migration and invasion of pancreatic ductal adenocarcinoma cells. Cyclic AMP is formed from cytosolic ATP by the enzyme adenylyl cyclase (AC). There are ten isoforms of ACs; nine are anchored in the plasma membrane and one is soluble. What remains unknown is the extent to which the expression of transmembrane AC isoforms is both modified in pancreatic cancer and mediates the inhibitory effect of forskolin on cell motility. Using real-time PCR analysis, ADCY3 was found to be highly expressed in pancreatic tumor tissues, resulting in a constitutive increase in cyclic AMP levels. On the other hand, ADCY2 was down-regulated. Migration, invasion, and filopodia formation in two different pancreatic adenocarcinoma cell lines, HPAC and PANC-1 deficient in AC1 or AC3, were studied. We found that AC3, upon stimulation with forskolin, enhanced cyclic AMP levels and inhibited cell migration and invasion. Unlikely to be due to a cytotoxic effect, the inhibitory effects of forskolin involved the quick formation of AC3/adenylyl cyclase-associated protein 1 (CAP1)/G-actin complex, which inhibited filopodia formation and cell motility. Using Western blotting analysis, forskolin, through AC3 activation, caused phosphorylation of CREB, but not ERK. The effect of CREB phosphorylation is likely to be associated with long-term signaling changes. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biological Sciences, Augusta University, Augusta, Georgia.
authors.forename: Sierra N
authors.initials: SN
authors.lastname: Quinn
authors.affiliation: Department of Biological Sciences, Augusta University, Augusta, Georgia.
authors.forename: Sarai H
authors.initials: SH
authors.lastname: Graves
authors.affiliation: Department of Biological Sciences, Augusta University, Augusta, Georgia.
authors.forename: Clayton
authors.initials: C
authors.lastname: Dains-McGahee
authors.affiliation: Department of Biological Sciences, Augusta University, Augusta, Georgia.
authors.forename: Emilee M
authors.initials: EM
authors.lastname: Friedman
authors.affiliation: Department of Biological Sciences, Augusta University, Augusta, Georgia.
authors.forename: Humma
authors.initials: H
authors.lastname: Hassan
authors.affiliation: Division of Abdominal Organ Transplantation, Department of Surgery, Pancreatic Islet Transplant Program, The University of Chicago Medical Center, Chicago, Illinois.
authors.forename: Piotr
authors.initials: P
authors.lastname: Witkowski
authors.affiliation: Department of Biological Sciences, Augusta University, Augusta, Georgia.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Sabbatini
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation
chemical_list: C489549:CAP1 protein, human; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D020536:Enzyme Activators; D034741:RNA, Small Interfering; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3; C106670:adenylyl cyclase 1
keywords: CAP1; adenylyl cyclase; forskolin; migration; pancreatic cancer