Radicicol-mediated inhibition of Bcr-Abl in K562 cells induced
p38-MAPK dependent erythroid differentiation and PU.1 down-regulation
Issue title: Integrated Functions of Diet in Anti-Aging and
Cancer Prevention: Papers from the 4th International Niigata Symposium on Diet
and Health, 20–30 November 2008, Niigata, Japan
Affiliations: Laboratoire de Biologie Moléculaire et
Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hôpital
Kirchberg, Luxembourg, Luxembourg
Note: [] Address for correspondence: Marc Diederich, Laboratoire de
Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg,
9, rue Edward Steichen, L-2540 Luxembourg, Luxemburg. Tel.: +352 2468 4040;
Fax: +352 2468 4060; E-mail: [email protected]
Abstract: Constitutive tyrosine kinase activity of the breakpoint cluster
region (Bcr)-Abl fusion protein is characteristic of chronic myelogenous
leukemia (CML). As resistance against Imatinib a Bcr-abl inhibitor used in CML,
was described, Heat shock protein (Hsp90) became an alternative target as
inhibition of Bcr-Abl-Hsp90 complex leads to proliferation arrest. Here, we
used natural product Radicicol (Rad), a macrocyclic antifungal, as an Hsp90
inhibitor to investigate the effect of Bcr-Abl inactivation on erythroid gene
expression and subsequently on the transcription factors involved in their
regulation. We showed that all erythroid genes studied were over-expressed
after Rad treatment while Bcr-Abl expression was inhibited. Specific
transcription factor NF-E2 was induced in Rad-treated cells as well as GATA-1
cofactors Friend of GATA (FOG)1 and SP1, whereas PU.1 was downregulated.
Moreover, p38 mitogen activated protein kinase (MAPK) inhibition prevented
Rad-mediated differentiation of K562 in correlation with decreased
γ-globin expression and suppression of Rad-mediated inhibition of PU.1.
In conclusion, our results show that Radicicol leads to Bcr-Abl inactivation
via Hsp90 inhibition inducing reactivation of the erythroid program in K562
cells.
