title: Activation of the EIF2α/ATF4 and ATF6 Pathways in DU-145 Cells by Boric Acid at the Concentration Reported in Men at the US Mean Boron Intake.
abstract: Fruits, nuts, legumes, and vegetables are rich sources of boron (B), an essential plant nutrient with chemopreventive properties. Blood boric acid (BA) levels reflect recent B intake, and men at the US mean intake have a reported non-fasting level of 10 μM. Treatment of DU-145 prostate cancer cells with physiological concentrations of BA inhibits cell proliferation without causing apoptosis and activates eukaryotic initiation factor 2 (eIF2α). EIF2α induces cell differentiation and protects cells by redirecting gene expression to manage endoplasmic reticulum stress. Our objective was to determine the temporal expression of endoplasmic reticulum (ER) stress-activated genes in DU-145 prostate cells treated with 10 μM BA. Immunoblots showed post-treatment increases in eIF2α protein at 30 min and ATF4 and ATF6 proteins at 1 h and 30 min, respectively. The increase in ATF4 was accompanied by an increase in the expression of its downstream genes growth arrest and DNA damage-induced protein 34 (GADD34) and homocysteine-induced ER protein (Herp), but a decrease in GADD153/CCAAT/enhancer-binding protein homologous protein (CHOP), a pro-apoptotic gene. The increase in ATF6 was accompanied by an increase in expression of its downstream genes GRP78/BiP, calreticulin, Grp94, and EDEM. BA did not activate IRE1 or induce cleavage of XBP1 mRNA, a target of IRE1. Low boron status has been associated with increased cancer risk, low bone mineralization, and retinal degeneration. ATF4 and BiP/GRP78 function in osteogenesis and bone remodeling, calreticulin is required for tumor suppressor p53 function and mineralization of teeth, and BiP/GRP78 and EDEM prevent the aggregation of misfolded opsins which leads to retinal degeneration. The identification of BA-activated genes that regulate its phenotypic effects provides a molecular underpinning for boron nutrition and biology.
authors: Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA.
authors: Sarah E
authors: SE
authors: Kobylewski
authors: Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA.
authors: Kimberly A
authors: KA
authors: Henderson
authors: Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA.
authors: Kristin E
authors: KE
authors: Yamada
authors: Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA. ceckhert@ucla.edu.|Department of Environmental Health Sciences, University of California, Fielding School of Public Health, 650 Charles E. Young Dr., Los Angeles, CA, 90095, USA. ceckhert@ucla.edu.
authors: Curtis D
authors: CD
authors: Eckhert
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D001888:Boric Acids / Q000008:administration & dosage* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D014407:Tumor Cells, Cultured; D014481:United States
chemical_list: D051702:Activating Transcription Factor 6; 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
keywords: ATF4; ATF6A; Boric acid; Boron; Calreticulin (CALR); DU-145; EDEM1; GADD153/CHOP (DDIT3); GADD34 (PPP1R15A); GRP78/BiP (HSPa5); GRP94 (HSP90B1); Herp (HERPUD1); Hrd1 (SYVN1); Nutrition; RE1 (ERN1); XBP1; eIF2α (EIF2A)