Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation

Derek James Hanson, Shingen Nakamura, Ryota Amachi, Masahiro Hiasa, Asuka Oda, Daisuke Tsuji, Kohji Itoh, Takeshi Harada, Kazuki Horikawa, Jumpei Teramachi, Hirokazu Miki, Toshio Matsumoto, Masahiro Abe

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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 a-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.

Original languageEnglish
Pages (from-to)33568-33586
Number of pages19
JournalOncotarget
Volume6
Issue number32
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Lactate
  • Metabolism
  • Monocarboxylate transporter
  • Multiple myeloma

ASJC Scopus subject areas

  • Oncology

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