QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.026245v1 70/6/2108    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fang, J. Articles by Wahl, M. L. Search for Related Content PubMed PubMed Citation Articles by Fang, J. Articles by Wahl, M. L.

The H⁺-Linked Monocarboxylate Transporter (MCT1/SLC16A1): A Potential Therapeutic Target for High-Risk Neuroblastoma

Department of Pathology, Duke University Medical Center, Durham, North Carolina (J.F., Q.J.Q., T.L.H., F.S., M.L.W.); and Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania (M.J.M., Q.W., H.Z., J.M.M.)

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 -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.

Received for publication May 4, 2006.

Accepted for publication September 25, 2006.

Address correspondence to: Miriam L. Wahl, Department of Pathology, Box, 3712, Duke University Medical Center, Durham, North Carolina 27710. E-mail: miriam.wahl{at}duke.edu

This article has been cited by other articles:

				S. HARGUINDEY, J. L. ARRANZ, M. L. WAHL, G. ORIVE, and S. J. RESHKIN Proton Transport Inhibitors as Potentially Selective Anticancer Drugs Anticancer Res, June 1, 2009; 29(6): 2127 - 2136. [Abstract] [Full Text] [PDF]

				M. G. Slomiany, G. D. Grass, A. D. Robertson, X. Y. Yang, B. L. Maria, C. Beeson, and B. P. Toole Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells Cancer Res., February 15, 2009; 69(4): 1293 - 1301. [Abstract] [Full Text] [PDF]

				S. M. Gallagher, J. J. Castorino, D. Wang, and N. J. Philp Monocarboxylate Transporter 4 Regulates Maturation and Trafficking of CD147 to the Plasma Membrane in the Metastatic Breast Cancer Cell Line MDA-MB-231 Cancer Res., May 1, 2007; 67(9): 4182 - 4189. [Abstract] [Full Text] [PDF]