RT Journal Article
SR Electronic
T1 The H<sup>+</sup>-Linked Monocarboxylate Transporter (MCT1/<em>SLC16A1</em>): A Potential Therapeutic Target for High-Risk Neuroblastoma
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 2108
OP 2115
DO 10.1124/mol.106.026245
VO 70
IS 6
A1 Fang, Jun
A1 Quinones, Quintin J.
A1 Holman, Trevor L.
A1 Morowitz, Michael J.
A1 Wang, Qun
A1 Zhao, Huaqing
A1 Sivo, Frank
A1 Maris, John M.
A1 Wahl, Miriam L.
YR 2006
UL http://molpharm.aspetjournals.org/content/70/6/2108.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics