Boric Acid Activated Pathways in Prostate DU‐145 Cells

Abstract

Boron intake is associated with reduced risk of prostate cancer and ultrasound determined gland volume. Boric acid (BA) at physiological concentrations is a reversible competitive inhibitor of cyclic ADP ribose (cADPR), depletes luminal endoplasmic reticulum Ca2+ and activates eIF2αP in DU‐145 prostate cells [Henderson and Eckhert 2009; 2006]. Our objective was to characterize the events that follow BA‐cADPR interaction. Treatment [10 μM BA] was followed by a dose dependent expansion of the ER and time dependent formation of TIA‐1 positive stress granules, decrease in global protein synthesis, and activation of the eIF2α/Grp78/ATF4 integrative stress pathway and the ATF6 branch of the unfolded protein response. BA increased expression of ATF4 downstream genes GADD34 and HERP and their respective proteins. CHOP, a pro‐apoptotic protein was decreased by BA treatment a result that is consistent with survival and differentiation. BA increased cytoplasmic ATF6 protein, its movement into the nucleus and downstream proteins Grp78, Grp94, calreticulin and XBP1. Cleavage of XBP1, an indicator of IRE1 activation, was not observed. HERP and EDEM1 mRNA were significantly up‐regulated by BA treatment. Our results extend current knowledge of the BA effect from rapid dose dependent inhibition of cADPR to time dependent activation of pathways known to be expressed in tissues affected by boron status. Funded by payments for teaching.