Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators.
Peroxisome proliferator activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily. Ligand activation of PPARgamma has been shown to cause growth arrest in several human tumor cell types, but the underlying molecular mechanism has not been elucidated. We report here that the PPARgamma ligand troglitazone (TRO) inhibited MCF-7 cell proliferation by blocking events critical for G1 --> S progression. Flow cytometry demonstrated that TRO at 20 microM increased the percentage of cells in G1 from 51 to 69% after 24 h. Accumulation of cells in G1 was accompanied by an attenuation of Rb protein phosphorylation associated with decreased CDK4 and CDK2 activities. Inhibition of CDK activity by TRO correlates with decreased protein levels for several G1 regulators of Rb phosphorylation (cyclin D1, and CDKs 2, 4, and 6). Overexpression of cyclin D1 partially rescued MCF-7 cells from TRO-mediated G1 arrest. Targeting of G1 regulatory proteins, particularly cyclin D1, and the resulting induction of G1 arrest by TRO may provide a novel antiproliferative therapy for human breast cancer.
Yin
F
F
Division of Endocrinology, Diabetes and Hypertension, UCLA School of Medicine, Los Angeles, California 90095, USA.
Wakino
S
S
Liu
Z
Z
Kim
S
S
Hsueh
W A
WA
Collins
A R
AR
Van Herle
A J
AJ
Law
R E
RE
D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002455:Cell Division; D002469:Cell Separation; D002470:Cell Survival; D002839:Chromans / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D008024:Ligands; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D017304:Annexin A5; D000970:Antineoplastic Agents; D002839:Chromans; D008024:Ligands; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D016160:Retinoblastoma Protein; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D019938:Cyclin D1; D000431:Ethanol; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D000077288:Troglitazone