title: Statin-dependent activation of protein kinase Cδ in acute promyelocytic leukemia cells and induction of leukemic cell differentiation.
abstract: Statins are HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibitors, which block the conversion of HMG-CoA to mevalonate and have potent cholesterol lowering properties. Beyond their importance in the generation of lipid lowering effects, the regulatory effects of statins on the mevalonate pathway have a significant impact on multiple other cellular functions. There is now extensive evidence that statins have anti-inflammatory and anti-neoplastic properties, but the precise mechanisms by which such responses are generated are not well understood. In the present study we demonstrate that statins engage a member of the protein kinase C (PKC) family of proteins, PKCδ, in acute promyelocytic leukemia (APL) cells. Our study shows that atorvastatin and fluvastatin induce proteolytic activation of PKCδ in the APL NB4 cell line, which expresses the t(15;17) translocation. Such engagement of PKCδ results in induction of its kinase domain and downstream regulation of pathways important for statin-dependent leukemia cell differentiation. Our research shows that the function of PKCδ is essential for statin-induced leukemic cell differentiation, as demonstrated by studies involving selective targeting of PKCδ using siRNAs. We also demonstrate that the potent enhancing effects of statins on all-trans retinoic acid (ATRA)-induced gene expression for CCL3 and CCL4 requires the function of PKCδ, suggesting a mechanism by which statins may promote ATRA-induced antileukemic responses. Altogether, our data establish a novel function for PKCδ as a mediator of statin-induced differentiation of APL cells and antileukemic effects.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology and Northwestern University Medical School, Chicago, IL 60611, USA. asassano.asassano.usa@northwestern.edu
authors.forename: Antonella
authors.initials: A
authors.lastname: Sassano
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.forename: Leo I
authors.initials: LI
authors.lastname: Gordon
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C515429:CCL3 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077340:Fluvastatin; D014212:Tretinoin; D000069059:Atorvastatin; D051745:Protein Kinase C-delta