TY - JOUR
T1 - Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma
AU - Aguirre, D.
AU - Boya, P.
AU - Bellet, D.
AU - Faivre, S.
AU - Troalen, F.
AU - Benard, J.
AU - Saulnier, P.
AU - Hopkins-Donaldson, S.
AU - Zangemeister-Wittke, U.
AU - Kroemer, G.
AU - Raymond, E.
N1 - Funding Information:
We thank Isabelle Pouillon, Nelly Motté and Jean Louis Bobot for their excellent technical assistance with cell cultures and quality control of mRNA analysis, and Heidi Lane, Novartis Institutes for BioMedical Research, for her critical reading of the manuscript. This work has been supported by a special grant from the Ligue contre le Cancer (to G.K.), as well as by grants from the European Commission (QLK3-CT-2002-01956 to G.K. and MCFI-2000-00943 to P.B.).
PY - 2004/12/1
Y1 - 2004/12/1
N2 - Molecular markers enabling the prediction of sensitivity/resistance to rapamycin may facilitate further clinical development of rapamycin and its derivatives as anticancer agents. In this study, several human ovarian cancer cell lines (IGROV1, OVCAR-3, A2780, SK-OV-3) were evaluated for susceptibility to rapamycin-mediated growth inhibition. The differential expression profiles of genes coding for proteins known to be involved in the mTOR signaling pathway, cell cycle control and apoptosis were studied before and after drug exposure by RT-PCR. In cells exposed to rapamycin, we observed a dose-dependent downregulation of CCND1 (cyclin D1) and CDK4 gene expression and late G1 cell cycle arrest. Among these cell lines, SK-OV-3 cells resistant to both rapamycin and RAD001 were the sole to show the expression of the anti-apoptotic gene Bcl-2. Bcl-2/bclxL-specific antisense oligonucleotides restored the sensitivity of SK-OV-3 cells to apoptosis induction by rapamycin and RAD001. These results indicate that baseline Bcl-2 expression and therapy-induced downexpression of CCND1 and CDK4 may be regarded as molecular markers enabling the prediction and follow-up of the cellular effects on cell cycle and apoptosis induction of rapamycin in ovarian cancer. Furthermore, strategies to down regulate Bcl-2 in ovarian cancer may prove useful in combination with rapamycin or RAD001 for ovarian cancer.
AB - Molecular markers enabling the prediction of sensitivity/resistance to rapamycin may facilitate further clinical development of rapamycin and its derivatives as anticancer agents. In this study, several human ovarian cancer cell lines (IGROV1, OVCAR-3, A2780, SK-OV-3) were evaluated for susceptibility to rapamycin-mediated growth inhibition. The differential expression profiles of genes coding for proteins known to be involved in the mTOR signaling pathway, cell cycle control and apoptosis were studied before and after drug exposure by RT-PCR. In cells exposed to rapamycin, we observed a dose-dependent downregulation of CCND1 (cyclin D1) and CDK4 gene expression and late G1 cell cycle arrest. Among these cell lines, SK-OV-3 cells resistant to both rapamycin and RAD001 were the sole to show the expression of the anti-apoptotic gene Bcl-2. Bcl-2/bclxL-specific antisense oligonucleotides restored the sensitivity of SK-OV-3 cells to apoptosis induction by rapamycin and RAD001. These results indicate that baseline Bcl-2 expression and therapy-induced downexpression of CCND1 and CDK4 may be regarded as molecular markers enabling the prediction and follow-up of the cellular effects on cell cycle and apoptosis induction of rapamycin in ovarian cancer. Furthermore, strategies to down regulate Bcl-2 in ovarian cancer may prove useful in combination with rapamycin or RAD001 for ovarian cancer.
KW - Apoptosis
KW - Cell cycle
KW - Gene expression
KW - RAD001
KW - Rapamycin
KW - Surrogate marker
UR - http://www.scopus.com/inward/record.url?scp=16444379884&partnerID=8YFLogxK
U2 - 10.1023/B:APPT.0000045781.46314.e2
DO - 10.1023/B:APPT.0000045781.46314.e2
M3 - Article
C2 - 15505422
AN - SCOPUS:16444379884
SN - 1360-8185
VL - 9
SP - 797
EP - 805
JO - Apoptosis
JF - Apoptosis
IS - 6
ER -