Bedin M, Geldanamycin ben AM, Saucier C, Mester J.
Geldanamycin, an inhibitor of the chaperone activity of HSP90,
induces MAPK-independent cell cycle arrest.
Int J Cancer. 2004 May 1;109(5):643-52
INSERM U482, Hôpital Saint-Antoine, 184 rue du Faubourg
St-Antoine, 75571 Paris Cedex 12, France.
bedin@st-antoine.inserm.fr
The effects of Geldanamycin , an ansamycin antibiotic in
development as a lead anticancer drug, were studied in mouse
BP-A31 fibroblasts and in human cancer-derived cell lines.
Geldanamycin and related molecules act by inhibiting the
chaperone function of the Hsp90 protein through competition for
ATP binding. The antiproliferative effects of Geldanamycin
have been attributed to destabilization of the Raf-1 protein,
one of the targets of Hsp90, and to the resulting inhibition of
MAPK. Addition of Geldanamycin to BP-A31 cells,
synchronously progressing through the G(1) phase, inhibited Rb
hyperphosphorylation and G(1)/S transition irrespective of the
time of addition. The G(1) arrest was accompanied by a
progressive decrease in Raf-1 content, especially of the
phosphorylated form; however, Geldanamycin caused only
partial inhibition of MAPK phosphorylation. We show that
Geldanamycin triggers a rapid and marked decrease in the
kinase activity of the cyclin E/cdk2 complex coupled with a
decline in both total and cdk2-associated cyclin E. In transient
transfection experiments, inhibition of cyclin E expression by
Geldanamycin was correlated with inhibition of the
transcriptional activity of the cyclin E gene promoter.
Inhibition of cdk4 activity by Geldanamycin was observed 3
hr after addition of the drug to late G(1) cells but not after a
short (1 hr) exposure, as revealed by the phosphorylation of Rb
on the Ser(780) residue. In human cancer-derived cell lines
expressing or not a functional Rb protein, Geldanamycin
blocked proliferation and inhibited the transcriptional activity
of the cyclin E gene promoter. In these cell lines, the
antiproliferative effect of Geldanamycin was not limited
to the G(1) phase, suggesting the existence of multiple cellular
targets of the drug. Copyright 2004 Wiley-Liss, Inc.
PMID: 14999769
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