Cyclic AMP in ovarian cancer cells both inhibits proliferation and increases c-KIT expression

TY - JOUR

T1 - Cyclic AMP in ovarian cancer cells both inhibits proliferation and increases c-KIT expression

AU - Shaw, Tanya J

AU - Keszthelyi, Eniko J

AU - Tonary, Angela M

AU - Cada, Michaela

AU - Vanderhyden, Barbara C

N1 - Copyright 2001 Elsevier Science.

PY - 2002/2/1

Y1 - 2002/2/1

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Benzamides

KW - Blotting, Northern

KW - Blotting, Western

KW - Cell Differentiation

KW - Cell Division

KW - Cell Membrane

KW - Cells, Cultured

KW - Cyclic AMP

KW - Female

KW - Humans

KW - Ovarian Neoplasms

KW - Phosphorylation

KW - Piperazines

KW - Precipitin Tests

KW - Proto-Oncogene Proteins c-kit

KW - Pyrimidines

KW - RNA, Messenger

KW - Rats

KW - Stem Cell Factor

U2 - 10.1006/excr.2001.5426

DO - 10.1006/excr.2001.5426

M3 - Article

C2 - 11795950

SN - 0014-4827

VL - 273

SP - 95

EP - 106

JO - Experimental Cell Research

JF - Experimental Cell Research

IS - 1

ER -