Radicicol-mediated inhibition of Bcr-Abl in K562 cells induced p38-MAPK dependent erythroid differentiation and PU.1 down-regulation.
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 gamma-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.
Morceau
Franck
F
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hôpital Kirchberg, Luxembourg, Luxembourg.
Buck
Isabelle
I
Dicato
Mario
M
Diederich
Marc
M
D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D000935:Antifungal Agents; D016044:Fusion Proteins, bcr-abl; D018942:Macrolides; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000099232:Proto-Oncogene Protein Spi-1; C035359:monorden