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 α-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.
Footnotes
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This work was supported by National Institutes of Health grants P01-CA56690 (to M.L.W.) and R01-CA87847 (to J.M.M.), The Abramson Family Cancer Research Institute (to J.M.M.), The Children's Oncology Group (to J.M.M.), an American Cancer Society Fellowship (to M.J.M.), and National Institutes of Health Medical Scientist Training Program grant T32-GM07171 (to Q.J.Q.).
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ABBREVIATIONS: MCT, monocarboxylate transporter; PCR, polymerase chain reaction; MTS, [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt]; C.SNARF-1AM, carboxyl semi-naphthyl rhodofluor-1 acetoxymethyl ester; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; Q-RT, quantitative real-time RT-PCR; RT-PCR, reverse transcription; ELISA, enzyme-linked immunosorbent assay; MYCN, transcription factor mycN; NB, neuroblastoma.
- Received May 4, 2006.
- Accepted September 25, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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