title: Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation.
abstract: Cancer cells robustly expel lactate produced through enhanced glycolysis via monocarboxylate transporters (MCTs) and maintain alkaline intracellular pH. To develop a novel therapeutic strategy against multiple myeloma (MM), which still remains incurable, we explored the impact of perturbing a metabolism via inhibiting MCTs. All MM cells tested constitutively expressed MCT1 and MCT4, and most expressed MCT2. Lactate export was substantially suppressed to induce death along with lowering intracellular pH in MM cells by blockade of all three MCT molecules with α-cyano-4-hydroxy cinnamate (CHC) or the MCT1 and MCT2 inhibitor AR-C155858 in combination with MCT4 knockdown, although only partially by knockdown of each MCT. CHC lowered intracellular pH and severely curtailed lactate secretion even when combined with metformin, which further lowered intracellular pH and enhanced cytotoxicity. Interestingly, an ambient acidic pH markedly enhanced CHC-mediated cytotoxicity, suggesting preferential targeting of MM cells in acidic MM bone lesions. Furthermore, treatment with CHC suppressed hexokinase II expression and ATP production to reduce side populations and colony formation. Finally, CHC caused downregulation of homing receptor CXCR4 and abrogated SDF-1-induced migration. Targeting tumor metabolism by MCT blockade therefore may become an effective therapeutic option for drug-resistant MM cells with elevated glycolysis.
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Derek James
authors.initials: DJ
authors.lastname: Hanson
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.|Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Amachi
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.|Department of Biomaterials and Bioengineering, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiasa
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.affiliation: Division of Bio-imaging, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Horikawa
authors.affiliation: Department of Histology and Oral Histology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Teramachi
authors.affiliation: Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003373:Coumaric Acids / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008687:Metformin / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors; D013876:Thiophenes / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D003373:Coumaric Acids; D008687:Metformin; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D013876:Thiophenes; D014498:Uracil; D000099233:Monocarboxylate Transport Protein 1; C546977:AR C155858; C406962:SLC16A4 protein, human; C490427:SLC16A7 protein, human; C007175:alpha-cyano-4-hydroxycinnamate
keywords: lactate; metabolism; monocarboxylate transporter; multiple myeloma