Regulation of intracellular pH in human melanoma

Potential therapeutic implications

Miriam L. Wahl, Judith A. Owen, Randy M Burd, Robin A. Herlands, Suzanne S. Nogami, Ulrich Rodeck, David Berd, Dennis B. Leeper, Charles S. Owen

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Melanoma cells in vivo maintain intracellular pH (pHi) in a viable range despite an extracellular tumor pH (pHe) that is typically below 7.0. In general, three families of transporters are capable of removing metabolic protons, but the specific transporters responsible for the maintenance of pHi at low pHe in melanomas have not been identified. Although the transporters exist in most cells, an inhibitor would be predicted to have selectivity for cells located in an acidic tumor bed because cells in that environment would be expected to have transporters chronically activated. In this report, the levels and extent of expression of the Na +/H+ exchanger (NHE-1) and two of the H+-linked monocarboxylate transporters (MCTs) were evaluated in three melanoma cell lines. The effects of inhibitors of each transporter were tested at an extracellular pH (pHe) of 7.3, 6.7, or 6.5 in melanoma cells that were grown at pHe 7.3 or 6.7. The activity of MCT isoform 1 (MCT-1) was up-regulated in three melanoma cell lines at low pHe, but that of NHE-1 was not. Furthermore, NHE-1 activity was lower in the melanomas than in other normal and malignant cell lines that were tested. Reverse transcription-PCR using primers specific for MCT-1, MCT-4, and NHE-1 showed that expression of none of these transporters was reproducibly upregulated at the level of transcription when cells were grown at pHe 6.7 instead of pHe 7.3. Ex vivo experiments using DB-1 human melanoma xenografts grown in severe combined immunodeficient mice found that MCT-1 and not NHE-1 was a major determinant of DB-1 tumor cell pHi. Taken together, the data indicate that MCTs are major determinants of pH regulation in melanoma. In contrast, keratinocytes and melanocytes under low pHe conditions relied on NHE-1. Inhibitors of MCTs thus have great potential to improve the effectiveness of chemotherapeutic drugs that work best at low pHi, such as alkylating agents and platinum-containing compounds, and they should be selective for cells in an acidic tumor bed. In most tissues, it is proposed that the NHE-1 could compensate for an inhibited MCT to prevent acidification, but in melanoma cells this did not occur. Therefore, MCT inhibitors may be particularly effective against malignant melanoma.

Original languageEnglish (US)
Pages (from-to)617-628
Number of pages12
JournalMolecular Cancer Therapeutics
Volume1
Issue number8
StatePublished - Jun 2002
Externally publishedYes

Fingerprint

Melanoma
Therapeutics
Cell Line
Neoplasms
Platinum Compounds
Sodium-Hydrogen Antiporter
SCID Mice
Alkylating Agents
Melanocytes
Keratinocytes
Heterografts
Reverse Transcription
Protons
Protein Isoforms
Maintenance
Polymerase Chain Reaction
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Wahl, M. L., Owen, J. A., Burd, R. M., Herlands, R. A., Nogami, S. S., Rodeck, U., ... Owen, C. S. (2002). Regulation of intracellular pH in human melanoma: Potential therapeutic implications. Molecular Cancer Therapeutics, 1(8), 617-628.

Regulation of intracellular pH in human melanoma : Potential therapeutic implications. / Wahl, Miriam L.; Owen, Judith A.; Burd, Randy M; Herlands, Robin A.; Nogami, Suzanne S.; Rodeck, Ulrich; Berd, David; Leeper, Dennis B.; Owen, Charles S.

In: Molecular Cancer Therapeutics, Vol. 1, No. 8, 06.2002, p. 617-628.

Research output: Contribution to journalArticle

Wahl, ML, Owen, JA, Burd, RM, Herlands, RA, Nogami, SS, Rodeck, U, Berd, D, Leeper, DB & Owen, CS 2002, 'Regulation of intracellular pH in human melanoma: Potential therapeutic implications', Molecular Cancer Therapeutics, vol. 1, no. 8, pp. 617-628.
Wahl ML, Owen JA, Burd RM, Herlands RA, Nogami SS, Rodeck U et al. Regulation of intracellular pH in human melanoma: Potential therapeutic implications. Molecular Cancer Therapeutics. 2002 Jun;1(8):617-628.
Wahl, Miriam L. ; Owen, Judith A. ; Burd, Randy M ; Herlands, Robin A. ; Nogami, Suzanne S. ; Rodeck, Ulrich ; Berd, David ; Leeper, Dennis B. ; Owen, Charles S. / Regulation of intracellular pH in human melanoma : Potential therapeutic implications. In: Molecular Cancer Therapeutics. 2002 ; Vol. 1, No. 8. pp. 617-628.
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