Inhibition of iron uptake is responsible for differential sensitivity to V-ATPase inhibitors in several cancer cell lines.
Many cell lines derived from tumors as well as transformed cell lines are far more sensitive to V-ATPase inhibitors than normal counterparts. The molecular mechanisms underlying these differences in sensitivity are not known. Using global gene expression data, we show that the most sensitive responses to HeLa cells to low doses of V-ATPase inhibitors involve genes responsive to decreasing intracellular iron or decreasing cholesterol and that sensitivity to iron uptake is an important determinant of V-ATPase sensitivity in several cancer cell lines. One of the most sensitive cell lines, melanoma derived SK-Mel-5, over-expresses the iron efflux transporter ferroportin and has decreased expression of proteins involved in iron uptake, suggesting that it actively suppresses cytoplasmic iron. SK-Mel-5 cells have increased production of reactive oxygen species and may be seeking to limit additional production of ROS by iron.
Straud
Sarah
S
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
Zubovych
Iryna
I
De Brabander
Jef K
JK
Roth
Michael G
MG
D000969:Antinematodal Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D018942:Macrolides / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D000098742:Ferroportin
D000969:Antinematodal Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D027682:Cation Transport Proteins; D018942:Macrolides; D017382:Reactive Oxygen Species; D000098742:Ferroportin; C057620:bafilomycin A; D002784:Cholesterol; D007501:Iron; D025262:Vacuolar Proton-Translocating ATPases