Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation
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Derek James Hanson1, Shingen Nakamura1, Ryota Amachi1,2, Masahiro Hiasa2,3, Asuka Oda1, Daisuke Tsuji1, Kohji Itoh1, Takeshi Harada1, Kazuki Horikawa4, Jumpei Teramachi5, Hirokazu Miki6, Toshio Matsumoto1 and Masahiro Abe1
1 Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
2 Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
3 Department of Biomaterials and Bioengineering, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
4 Division of Bio-imaging, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
5 Department of Histology and Oral Histology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
6 Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan
Masahiro Abe, email:
Keywords: multiple myeloma, monocarboxylate transporter, lactate, metabolism
Received: February 23, 2015 Accepted: August 26, 2015 Published: September 10, 2015
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.
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