Inhibition of Iron Uptake Is Responsible for Differential Sensitivity to V-ATPase Inhibitors in Several Cancer Cell Lines

Abstract

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.

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

“…To determine whether the increased LC3-II:LC3-I ratio was due to an overall increase in autophagy or a block in autophagosome turnover, we treated the cells with bafilomycin A 1 (Baf) to inhibit autophagic flux. 26 Since Baf can potentially disrupt the endocytic trafficking of TF, we also used chloroquine 29 and found that the LC3-II:LC3-I ratio was higher in cells treated with iron and either Baf or chloroquine than in cells treated with Baf or chloroquine alone (Fig. 1B and C).…”

Intracellular Proton Pumps as Targets in Chemotherapy: V-ATPases and Cancer

“…Using global gene expression data Straud et al found that the increased sensitivity to V-ATPase inhibitors observed in cancer cells was correlated to their greater dependence on iron uptake, presumably to compensate their ROS production [113]. Wnt/ -catenin pathway is an important tumourigenic signal in many cancer cell types, e.g.…”

Iron loading and oxidative stress in theAtm−/−mouse liver

“…Alongside its contribution to neurodegeneration, increased intracellular iron and the resultant OS can also potentiate tumor development (10,12,23,24,29,38). Ironically, after contributing to the insult that initiated tumor development, increased cellular iron is then a critical element required for the continued growth of tumors in a number of different cancer types (10,12,23,24,38).…”

“…Ironically, after contributing to the insult that initiated tumor development, increased cellular iron is then a critical element required for the continued growth of tumors in a number of different cancer types (10,12,23,24,38). A-T patients are predisposed to a variety of cancers, with one of the most significant clinical features of A-T disease being the incidence of lymphoid tumors that develop in ϳ30% of A-T patients (for review, see Ref.…”