Published ahead of print on December 30, 2004, doi:10.1165/rcmb.2004-0133OC Am. J. Respir. Cell Mol. Biol., Volume 32, Number 5, May 2005, 436-442 A more recent version of this article appeared on May 1, 2005
Submitted on April 27, 2004 Role of Iron in Inactivation of EGFR After Asbestos Treatment of Human Lung and Pleural Target CellsAleksander Baldys1 and Ann E Aust1*1 Department of Chemistry and Biochemistry, Utah State University, Logan, UT, USA * To whom correspondence should be addressed. E-mail: aaust{at}cc.usu.edu.
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 µg/cm2) in A549 cells. Exposure of A549 cells to 6 µg/cm2 crocidolite for 3 to 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. Most importantly, 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.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
