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Originally published In Press as doi:10.1074/jbc.M111497200 on January 25, 2002

J. Biol. Chem., Vol. 277, Issue 17, 14821-14828, April 26, 2002
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Abnormal Acidification of Melanoma Cells Induces Tyrosinase Retention in the Early Secretory Pathway*

Ruth HalabanDagger §, Robin S. Patton, Elaine ChengDagger , Sherri Svedine, E. Sergio Trombetta||, Miriam L. Wahl**, Stephen AriyanDagger Dagger , and Daniel N. Hebert§§

From the Departments of Dagger  Dermatology, || Cell Biology, and Dagger Dagger  Plastic Surgery, Yale University School of Medicine, New Haven, Connecticut 06520, the  Department of Biochemistry and Molecular Biology, Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, Massachusetts 01003, and the ** Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

In tyrosinase-positive amelanotic melanoma cells, inactive tyrosinase accumulates in the endoplasmic reticulum. Based on studies described here, we propose that aberrant vacuolar proton ATPase (V-ATPase)-mediated proton transport in melanoma cells disrupts tyrosinase trafficking through the secretory pathway. Amelanotic but not melanotic melanoma cells or normal melanocytes display elevated proton export as observed by the acidification of the extracellular medium and their ability to maintain neutral intracellular pH. Tyrosinase activity and transit through the Golgi were restored by either maintaining the melanoma cells in alkaline medium (pH 7.4-7.7) or by restricting glucose uptake. The translocation of tyrosinase out of the endoplasmic reticulum and the induction of cell pigmentation in the presence of the ionophore monensin or the specific V-ATPase inhibitors concanamycin A and bafilomycin A1 supported a role for V-ATPases in this process. Because it was previously shown that V-ATPase activity is increased in solid tumors in response to an acidified environment, the appearance of hypopigmented cells in tyrosinase-positive melanoma tumors may indicate the onset of enhanced glycolysis and extracellular acidification, conditions known to favor metastatic spread and resistance to weak base chemotherapeutic drugs.

* This work was supported by U. S. Public Health Service Grants AR39848 and CA44542 (to R. H.), AR41942 (to R. E. Tigelaar, Yale Skin Diseases Research Center), and CA79864 (to D. N. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence may be addressed: Dept. of Dermatology, Yale University School of Medicine, P. O. Box 208059, HRT 610, 15 York St., New Haven, CT 06520-8059. Tel.: 203-785-4352; Fax: 203-785-7637; E-mail: ruth.halaban@yale.edu.

§§ To whom correspondence may be addressed: Dept. of Biochemistry & Molecular Biology, University of Massachusetts, Lederle Graduate Research Tower, 818, Box 34505, Amherst, MA 01003. Tel.: 413-545-0079; Fax: 413-545-3291; dhebert@biochem.umass.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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