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.