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: Tanya J Shaw, Eniko J Keszthelyi, Angela M Tonary, Michaela Cada, Barbara C Vanderhyden
• Journal: Experimental cell research (Exp Cell Res) Vol. 273 Issue 1 Pg. 95-106 (Feb 01 2002) ISSN: 0014-4827 [Print] United States
• PMID: 11795950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2001 Elsevier Science.

Chemical References

• Benzamides
• Piperazines
• Pyrimidines
• RNA, Messenger
• Stem Cell Factor
• Imatinib Mesylate
• Cyclic AMP
• Proto-Oncogene Proteins c-kit

Topics

• Animals
• Apoptosis
• Benzamides
• Blotting, Northern
• Blotting, Western
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Cell Membrane (physiology)
• Cells, Cultured (drug effects, metabolism)
• Cyclic AMP (pharmacology)
• Female
• Humans
• Imatinib Mesylate
• Ovarian Neoplasms (metabolism, pathology)
• Phosphorylation
• Piperazines
• Precipitin Tests
• Proto-Oncogene Proteins c-kit (genetics, metabolism)
• Pyrimidines (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Stem Cell Factor (genetics, metabolism)