The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells.
Bottom Line: A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored.Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild-type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full-length protein.APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment.
Affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. Electronic address: email@example.com.Show MeSH
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Mentions: Finally, we examined the role of the copper binding domain (CuBD) in the E1 extracellular domain of APP. We generated a construct (APPΔCuE1) in which three histidines were mutated to alanine in a key area of the protein associated with copper binding  (Fig. 4A). This construct was expressed and processed in DU145 cells in a manner identical to that of wild-type APP695 (Fig. 4B). However, APPΔCuE1 failed to mitigate copper-induced growth inhibition (Fig. 4C) indicating that the extracellular E1 CuBD, in addition to the cytosolic domain, of APP were prerequisites in this respect.
Affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK. Electronic address: firstname.lastname@example.org.