Role of iron in inactivation of epidermal growth factor receptor after asbestos treatment of human lung and pleural target cells.
Although the mechanism by which asbestos causes cancer remains unknown, iron associated with asbestos is thought to play a role in the pathogenic effects of fibers. Here, we examined the effects of asbestos on the epidermal growth factor receptor (EGFR) in human lung epithelial (A549) cells, human pleural mesothelial (MET5A) cells, and normal human small airway epithelial (SAEC) cells. Treatment of A549, MET5A, and SAEC cells with asbestos caused a significant reduction of EGFR tyrosine phosphorylation. This was both time- (15 min to 24 h) and concentration-dependent (1.5, 3, and 6 mug/cm(2)) in A549 cells. Also, treatment with 6 mug/cm(2) crocidolite for 24 h diminished the phosphorylation levels of human EGFR 2 (HER2). Exposure of A549 cells to 6 mug/cm(2) crocidolite for 3-24 h resulted in no detectable Y1045 phosphorylation and no apparent degradation of the EGFR. Inhibition of fiber endocytosis resulted in a considerable inhibition of EGFR dephosphorylation. Removal of iron from asbestos by desferrioxamine B or phytic acid inhibited asbestos-induced decreases in EGFR phosphorylation. The effects of crocidolite, amosite, and chrysotile on the EGFR phosphorylation state appeared to be directly related to the amount of iron mobilized from these fibers. These results strongly suggest that iron plays an important role in asbestos-induced inactivation of EGFR.
Baldys
Aleksander
A
Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322-0300, USA. AAUST@cc.usu.edu
Aust
Ann E
AE
D001194:Asbestos / Q000633:toxicity*; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D003571:Cytochalasin B / Q000378:metabolism; D015638:Cytochalasin D / Q000378:metabolism; D003676:Deferoxamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000187:drug effects*; D019016:Mineral Fibers / Q000633:toxicity*; D010766:Phosphorylation; D010833:Phytic Acid / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
D001194:Asbestos; D017638:Asbestos, Crocidolite; D002273:Carcinogens; D003571:Cytochalasin B; D015638:Cytochalasin D; D003676:Deferoxamine; D066246:ErbB Receptors; D007501:Iron; D007502:Iron Chelating Agents; D019016:Mineral Fibers; D010833:Phytic Acid; D018719:Erb-b2 Receptor Tyrosine Kinases