title: The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma.
abstract: Neuroblastomas produce high amounts of lactic acid and upregulate the H(+)-linked monocarboxylate transporter isoform 1 (MCT1/SLC16A1). We found elevated MCT1 mRNA levels in fresh neuroblastoma biopsy samples that correlated positively with risk of fatal disease and amplification of the "proto-oncogenic" transcription factor MYCN. We further investigated MCT as a potential therapeutic target in vitro. The neuroblastoma cell lines evaluated were Sk-N-SH, CHP134, IMR32, and NGP. All lines exhibited decreased intracellular pH at low tumor-like extracellular pH. Lonidamine or exogenous lactate further lowered intracellular pH. Immediate early lowering of intracellular pH with lonidamine or lactate at extracellular pH 6.5 correlated positively with diminished cell viability within 48 h. These findings indicate that MCT1 is a potential therapeutic target and that neuroblastoma therapy may be enhanced by therapeutic strategies to inhibit or overwhelm MCT. Additional experiments indicated that the mechanism of cell death by lonidamine or exogenous lactate is similar to that obtained using alpha-cyano-4-OH-cinnamate, a well established MCT inhibitor. Because lactate production is also high in melanoma and many other tumor types, MCT inhibitors may have broad application in cancer treatment. Such treatment would have selectivity by virtue of the acidic milieu surrounding tumors, because MCT is increasingly active as extracellular pH decreases below 7.0 and lactic acid production increases.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Quintin J
authors.initials: QJ
authors.lastname: Quinones
authors.forename: Trevor L
authors.initials: TL
authors.lastname: Holman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morowitz
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhao
authors.forename: Frank
authors.initials: F
authors.lastname: Sivo
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Miriam L
authors.initials: ML
authors.lastname: Wahl
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011522:Protons; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D027501:Monocarboxylic Acid Transporters; D011522:Protons; D012333:RNA, Messenger; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1