Regulation of leukemic cell differentiation and retinoid-induced gene expression by statins.
There is emerging evidence that, beyond their cholesterol-lowering properties, statins exhibit important antileukemic effects in vitro and in vivo, but the precise mechanisms by which they generate such responses remain to be determined. We have previously shown that statins promote differentiation of acute promyelocytic leukemia cells and enhance generation of all-trans retinoic acid (ATRA)-dependent antileukemic responses. We now provide evidence that statin-dependent leukemic cell differentiation requires engagement and activation of the c-Jun NH2-terminal kinase kinase pathway. In addition, in experiments, to define the molecular targets and mediators of statin-induced differentiation, we found a remarkable effect of statins on ATRA-dependent gene transcription, evidenced by the selective induction of over 400 genes by the combination of atorvastatin and ATRA. Altogether, our studies identify novel statin molecular targets linked to differentiation, establish that statins modulate ATRA-dependent transcription, and suggest that combined use of statins with retinoids may provide a novel approach to enhance antileukemic responses in acute promyelocytic leukemia and possibly other leukemias.
Sassano
Antonella
A
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611, USA.
Lo Iacono
Marco
M
Antico
Giovanni
G
Jordan
Alison
A
Uddin
Shahab
S
Calogero
Raffaele A
RA
Platanias
Leonidas C
LC
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000069059:Atorvastatin; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012176:Retinoids; D014212:Tretinoin; D000069059:Atorvastatin