title: Cyclic AMP in ovarian cancer cells both inhibits proliferation and increases c-KIT expression.
abstract: C-KIT encodes a tyrosine kinase receptor (KIT) that, when activated by its ligand (KL), stimulates proliferation, differentiation, migration, and survival. Greater than 70% of epithelial ovarian cancers coexpress c-KIT and KL. C-KIT and KL expression levels have been shown to be up-regulated by cAMP in some cell types. Additionally, cAMP is well-recognized for its anti-proliferative effects in cancer cells. The goal of these experiments was to investigate these seemingly contradictory consequences of cAMP treatment by: (1) confirming the growth inhibitory actions of cAMP on ovarian cancer cells; (2) investigating the ability of cAMP to affect c-KIT and KL expression in these cells; and (3) examining the possible role of endogenous and/or cAMP-regulated c-KIT and KL expression in ovarian cancer cell proliferation. HEY cells, an ovarian cancer cell line which expresses c-KIT and KL, were treated with dibutyryl cyclic AMP (dbcAMP), 8-bromo-cAMP, and cholera toxin over a range of concentrations. With all treatments, stimulation of cAMP signaling caused a dose-dependent inhibition of HEY cell proliferation by up to 40, 62, and 38%, respectively. This inhibition of proliferation correlated with a dose-dependent increase in c-KIT mRNA expression, yielding 4- to 7-fold elevations in transcript abundance; there were no changes in steady-state levels of KL transcripts. In order to determine whether KIT expression/activity was responsible for the observed decrease in proliferation, dbcAMP-treated HEY cells were exposed either to anti-KIT neutralizing antibodies or to the KIT inhibitor STI571. These experiments demonstrated that KIT inhibition did not alter the growth rate of cells or reverse the dbcAMP-induced inhibition of proliferation. These results suggest that cAMP signaling pathways regulate both cell proliferation and c-KIT expression in ovarian cancer cells; however, KIT is not assuming its well-established role as a growth factor.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 1C4, Canada.
authors.forename: Tanya J
authors.initials: TJ
authors.lastname: Shaw
authors.forename: Eniko J
authors.initials: EJ
authors.lastname: Keszthelyi
authors.forename: Angela M
authors.initials: AM
authors.lastname: Tonary
authors.forename: Michaela
authors.initials: M
authors.lastname: Cada
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Vanderhyden
mesh_terms: D000818:Animals; D017209:Apoptosis; D001549:Benzamides; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines; D011233:Precipitin Tests; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D000242:Cyclic AMP; D019009:Proto-Oncogene Proteins c-kit