title: GSK-3 Inhibition Sensitizes Acute Myeloid Leukemia Cells to 1,25D-Mediated Differentiation.
abstract: 1,25-dihydroxyvitamin D3 (1,25D), the biologically active form of vitamin D, is widely considered a promising therapy for acute myeloid leukemia (AML) based on its ability to drive differentiation of leukemic cells. However, clinical trials have been disappointing in part to dose-limiting hypercalcemia. Here we show how inhibiting glycogen synthase kinase 3 (GSK3) can improve the differentiation response of AML cells to 1,25D-mediated differentiation. GSK3 inhibition in AML cells enhanced the differentiating effects of low concentrations of 1,25D. In addition, GSK3 inhibition augmented the ability of 1,25D to induce irreversible growth inhibition and slow the progression of AML in mouse models. Mechanistic studies revealed that GSK3 inhibition led to the hyperphosphorylation of the vitamin D receptor (VDR), enabling an interaction between VDR and the coactivator, SRC-3 (NCOA3), thereby increasing transcriptional activity. We also found that activation of JNK-mediated pathways in response to GSK3 inhibition contributed to the potentiation of 1,25D-induced differentiation. Taken together, our findings offer a preclinical rationale to explore the repositioning of GSK3 inhibitors to enhance differentiation-based therapy for AML treatment. Cancer Res; 76(9); 2743-53. ©2016 AACR.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Tammy
authors.initials: T
authors.lastname: Stefan
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: James
authors.initials: J
authors.lastname: Ignatz-Hoover
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio. Invenio Therapeutics, Cleveland, Ohio.
authors.forename: Stephen
authors.initials: S
authors.lastname: Moreton
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Gary
authors.initials: G
authors.lastname: Parizher
authors.affiliation: Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio. Invenio Therapeutics, Cleveland, Ohio. University Hospitals Case Medical Center, Cleveland, Ohio. dnw@case.edu.
authors.forename: David N
authors.initials: DN
authors.lastname: Wald
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D051379:Mice; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D018167:Receptors, Calcitriol; C579457:VDR protein, human; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D038362:Glycogen Synthase Kinase 3; D002117:Calcitriol