Auranofin promotes retinoic acid- or dihydroxyvitamin D3-mediated cell differentiation of promyelocytic leukaemia cells by increasing histone acetylation.
OBJECTIVE
To investigate the molecular mechanism for the effect of auranofin on the induction of cell differentiation, the cellular events associated with differentiation were analysed in acute promyelocytic leukaemia (APL) cells.


METHODS
The APL blasts from leukaemia patients and NB4 cells were cotreated with auroanofin and all-trans-retinoic acid (ATRA) at suboptimal concentration. The HL-60 cells were treated with auroanofin and a subeffective dose of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2 vit D3) in combination. The effect of auroanofin was investigated on histone acetylation at the promoter of differentiation-associated genes and expression of cell cycle regulators.


RESULTS
Treatment with auroanofin and ATRA cooperatively induced granulocytic differentiation of fresh APL blasts isolated from patients and NB4 cells. The combined treatment also increased reorganization of nuclear PML bodies and histone acetylation at the promoter of the RARbeta2 gene. Auroanofin also promoted monocytic differentiation of the HL-60 cells triggered by subeffective concentration of 1,25(OH)2 vit D3. The combined treatment of auroanofin and 1,25(OH)2 vit D3 stimulated histone acetylation at p21 promoters and increased the accumulation of cells in the G0/G1 phase. Consistent with this, the expressions of p21, p27 and PTEN were increased and the levels of cyclin A, Cdk2 and Cdk4 were decreased. Furthermore, the hypophosphorylated form of pRb was markedly increased in cotreated cells.


CONCLUSIONS
These findings indicate that auroanofin in combination with low doses of either ATRA or 1,25(OH)2 vit D3 promotes APL cell differentiation by enhancing histone acetylation and the expression of differentiation-associated genes.
Park
S J
SJ
1Department of Natural Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Kim
M
M
Kim
N H
NH
Oh
M K
MK
Cho
J K
JK
Jin
J Y
JY
Kim
I S
IS
D000107:Acetylation / Q000187:drug effects; D000328:Adult; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D015153:Blotting, Western; D002117:Calcitriol / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002648:Child; D002843:Chromatin / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000502:physiology*
D018501:Antirheumatic Agents; D002843:Chromatin; D006657:Histones; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082925:retinoic acid receptor beta; D001310:Auranofin; D014212:Tretinoin; D015689:Oncogene Protein p21(ras); D002117:Calcitriol