title: Perturbation of energy metabolism by fatty-acid derivative AIC-47 and imatinib in BCR-ABL-harboring leukemic cells.
abstract: In Ph-positive leukemia, imatinib brought marked clinical improvement; however, further improvement is needed to prevent relapse. Cancer cells efficiently use limited energy sources, and drugs targeting cellular metabolism improve the efficacy of therapy. In this study, we characterized the effects of novel anti-cancer fatty-acid derivative AIC-47 and imatinib, focusing on cancer-specific energy metabolism in chronic myeloid leukemia cells. AIC-47 and imatinib in combination exhibited a significant synergic cytotoxicity. Imatinib inhibited only the phosphorylation of BCR-ABL; whereas AIC-47 suppressed the expression of the protein itself. Both AIC-47 and imatinib modulated the expression of pyruvate kinase M (PKM) isoforms from PKM2 to PKM1 through the down-regulation of polypyrimidine tract-binding protein 1 (PTBP1). PTBP1 functions as alternative splicing repressor of PKM1, resulting in expression of PKM2, which is an inactive form of pyruvate kinase for the last step of glycolysis. Although inactivation of BCR-ABL by imatinib strongly suppressed glycolysis, compensatory fatty-acid oxidation (FAO) activation supported glucose-independent cell survival by up-regulating CPT1C, the rate-limiting FAO enzyme. In contrast, AIC-47 inhibited the expression of CPT1C and directly fatty-acid metabolism. These findings were also observed in the CD34(+) fraction of Ph-positive acute lymphoblastic leukemia cells. These results suggest that AIC-47 in combination with imatinib strengthened the attack on cancer energy metabolism, in terms of both glycolysis and compensatory activation of FAO.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: t3501002@edu.gifu-u.ac.jp.
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Kumazaki
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Department of Anatomy and Biology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 596-8686, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Sugito
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuranaga
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Anatomy and Biology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 596-8686, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.affiliation: National Hospital Organization Nagoya Medical Center, 4-1-1 Sannnomaru, Naka-ku, Nagoya 460-0001, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D005227:Fatty Acids / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D007659:Ketones / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D014162:Transfection
chemical_list: C000607609:1-(azocan-1-yl)dec-3-en-1one; D018952:Antigens, CD34; C581634:BCR-ABL1 fusion protein, human; D005227:Fatty Acids; D006573:Heterocyclic Compounds, 1-Ring; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007659:Ketones; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; C450006:PTBP1 protein, human; D047428:Protein Kinase Inhibitors; D038941:Polypyrimidine Tract-Binding Protein; D000068877:Imatinib Mesylate; D011770:Pyruvate Kinase; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL; CPT1C; Fatty-acid oxidation; Imatinib; Warburg effect