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.

Autor: Kobylewski SE; Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA., Henderson KA; Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA., Yamada KE; Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA., Eckhert CD; 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.
Jazyk: angličtina
Zdroj: Biological trace element research [Biol Trace Elem Res] 2017 Apr; Vol. 176 (2), pp. 278-293. Date of Electronic Publication: 2016 Sep 01.
DOI: 10.1007/s12011-016-0824-y
Abstrakt: 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.
Databáze: MEDLINE
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