Abnormal acidification of melanoma cells induces tyrosinase retention in the early secretory pathway.
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.
Halaban
Ruth
R
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ruth.halaban@yale.edu
Patton
Robin S
RS
Cheng
Elaine
E
Svedine
Sherri
S
Trombetta
E Sergio
ES
Wahl
Miriam L
ML
Ariyan
Stephen
S
Hebert
Daniel N
DN
D000143:Acids / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006056:Golgi Apparatus / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018942:Macrolides; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000143:Acids; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; C036978:concanamycin A; C040929:bafilomycin A1; D014442:Monophenol Monooxygenase; D025262:Vacuolar Proton-Translocating ATPases; D005947:Glucose