Boric acid induces cytoplasmic stress granule formation, eIF2α phosphorylation, and ATF4 in prostate DU-145 cells

Dietary boron intake is associated with reduced prostate and lung cancer risk and increased bone mass. Boron is absorbed and circulated as boric acid (BA) and at physiological concentrations is a reversible competitive inhibitor of cyclic ADP ribose, the endogenous agonist of the ryanodine receptor calcium (Ca+2) channel, and lowers endoplasmic reticulum (ER) [Ca]. Low ER [Ca2+] has been reported to induce ER stress and activate the eIF2 alpha/ATF4 pathway. Here we report that treatment of DU145 prostate cells with physiological levels of BA induces ER stress with the formation of stress granules and mild activation of eIF2 alpha, GRP78/BiP, and ATF4. Mild activation of eIF2 alpha and its downstream transcription factor, ATF4, enables cells to reconfigure gene expression to manage stress conditions and mild activation of ATF4 is also required for the differentiation of osteoblast cells. Our results using physiological levels of boric acid identify the eIF2 alpha/ATF pathway as a plausible mode of action that underpins the reported health effects of dietary boron.