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First published on September 25, 2006; DOI: 10.1124/mol.106.026245

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Received for publication May 4, 2006.
Revised September 25, 2006.
Accepted for publication September 25, 2006.

The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high- risk neuroblastoma

Jun Fang 1, Quintin J Quinones 2, Trevor L Holman 2, Michael J Morowitz 3, Qun Wang 3, Huaquing Zhao 3, Frank Sivo 4, John M Maris 3, Miriam L Wahl 1*

1 Duke University 2 Duke U 3 Children's Hospital of Philadelphia 4 Columbia U.

* Address correspondence to: E-mail: miriam.wahl{at}duke.edu

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, which correlated positively with risk of fatal disease and amplification of the "protooncogenic" 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. Intracellular pH was lowered further by lonidamine or exogenous lactate. 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 (CNCn), 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, since MCT is increasingly active as extracellular pH decreases below 7.0 and lactic acid production increases.


Key words: Fluorescence techniques, Mechanisms of cell killing/apoptosis


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