title: Boric acid induces cytoplasmic stress granule formation, eIF2α phosphorylation, and ATF4 in prostate DU-145 cells.
abstract: 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(2+)]. Low ER [Ca(2+)] has been reported to induce ER stress and activate the eIF2α/ATF4 pathway. Here we report that treatment of DU-145 prostate cells with physiological levels of BA induces ER stress with the formation of stress granules and mild activation of eIF2α, GRP78/BiP, and ATF4. Mild activation of eIF2α 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 eIF2α/ATF pathway as a plausible mode of action that underpins the reported health effects of dietary boron.
authors.affiliation: Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Henderson
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kobylewski
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Yamada
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Eckhert
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D001888:Boric Acids / Q000633:toxicity*; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D001888:Boric Acids; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D051701:Activating Transcription Factor 4; C032688:boric acid