Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 286, Issue 5, Pages 916-922Publisher
ACADEMIC PRESS INC
DOI: 10.1006/bbrc.2001.5491
Keywords
troglitazone; breast cancer cell; G1 arrest; cyclin D1; pRb; CDKs
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Peroxisome proliferator activated receptor gamma (PPAR gamma) is a member of the nuclear receptor superfamily. Ligand activation of PPAR gamma 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 PPAR gamma ligand troglitazone (TRO) inhibited MCF-7 cell proliferation by blocking events critical for G1 -->S progression. Flow cytometry demonstrated that TRO at 20 muM 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. Inhibit-ion of CDK activity by THO correlates with decreased protein levels for several G1 regulators of Rb phosphorylation (cyclin D1, and CDKs 2, 4, and 6). Overexpression of cyclin DI partially rescued MCF-7 cells from TRO-mediated G1 arrest. Targeting of G1 regulatory proteins, particularly cyclin D1, and the resulting inducation of G1 arrest by TRO may provide a novel antiproliferative therapy for human breast cancer. (C) 2001 Academic Press.
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