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

Henderson KA, Kobylewski SE, Yamada KE, Eckhert CD - Biometals (2014)

Bottom Line: Low ER [Ca(2+)] has been reported to induce ER stress and activate the eIF2α/ATF4 pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA.

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.

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Related in: MedlinePlus

The cell cycle was not significantly altered by BA treatment. Flow cytometry analysis was conducted a 24 h treatment with 0 or 50 µM BA. The percent of cells treated with 0 or 50 µM BA were: G1 phase 50.59 ± 0.75 and 51.21 ± 0.62 %, S phase 13.09 ± 1.16 and 15.15 ± 0.38 %, G2 phase 32.09 ± 0.46 and 31.53 ± 0.18 % respectively, (n = 3). The 2 % shift in S phase was of doubtful biological significance. Standard deviation error bars were plotted, but are too close to the bar graph to visualize
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Fig4: The cell cycle was not significantly altered by BA treatment. Flow cytometry analysis was conducted a 24 h treatment with 0 or 50 µM BA. The percent of cells treated with 0 or 50 µM BA were: G1 phase 50.59 ± 0.75 and 51.21 ± 0.62 %, S phase 13.09 ± 1.16 and 15.15 ± 0.38 %, G2 phase 32.09 ± 0.46 and 31.53 ± 0.18 % respectively, (n = 3). The 2 % shift in S phase was of doubtful biological significance. Standard deviation error bars were plotted, but are too close to the bar graph to visualize

Mentions: Flow cytometry analysis following a 24 h treatment with 50 µM BA had little impact on the cell cycle. The percent of cells treated with 0 or 50 µM BA were: G1 phase 50.59 ± 0.75 and 51.21 ± 0.62 %, S phase 13.09 ± 1.16 and 15.15 ± 0.38 %, G2 phase 32.09 ± 0.46 and 31.53 ± 0.18 % respectively (Fig. 4). The 2 % shift in S phase (p value = 0.03) was so small it was doubtful it had biological meaning. This result is consistent with previous reports demonstrating that BA does not cause a biologically significant effect on the cell cycle (Barranco and Eckhert 2004; Bradke et al. 2008). We did not observe an apoptotic cell population after BA treatment.Fig. 4


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

Henderson KA, Kobylewski SE, Yamada KE, Eckhert CD - Biometals (2014)

The cell cycle was not significantly altered by BA treatment. Flow cytometry analysis was conducted a 24 h treatment with 0 or 50 µM BA. The percent of cells treated with 0 or 50 µM BA were: G1 phase 50.59 ± 0.75 and 51.21 ± 0.62 %, S phase 13.09 ± 1.16 and 15.15 ± 0.38 %, G2 phase 32.09 ± 0.46 and 31.53 ± 0.18 % respectively, (n = 3). The 2 % shift in S phase was of doubtful biological significance. Standard deviation error bars were plotted, but are too close to the bar graph to visualize
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4300416&req=5

Fig4: The cell cycle was not significantly altered by BA treatment. Flow cytometry analysis was conducted a 24 h treatment with 0 or 50 µM BA. The percent of cells treated with 0 or 50 µM BA were: G1 phase 50.59 ± 0.75 and 51.21 ± 0.62 %, S phase 13.09 ± 1.16 and 15.15 ± 0.38 %, G2 phase 32.09 ± 0.46 and 31.53 ± 0.18 % respectively, (n = 3). The 2 % shift in S phase was of doubtful biological significance. Standard deviation error bars were plotted, but are too close to the bar graph to visualize
Mentions: Flow cytometry analysis following a 24 h treatment with 50 µM BA had little impact on the cell cycle. The percent of cells treated with 0 or 50 µM BA were: G1 phase 50.59 ± 0.75 and 51.21 ± 0.62 %, S phase 13.09 ± 1.16 and 15.15 ± 0.38 %, G2 phase 32.09 ± 0.46 and 31.53 ± 0.18 % respectively (Fig. 4). The 2 % shift in S phase (p value = 0.03) was so small it was doubtful it had biological meaning. This result is consistent with previous reports demonstrating that BA does not cause a biologically significant effect on the cell cycle (Barranco and Eckhert 2004; Bradke et al. 2008). We did not observe an apoptotic cell population after BA treatment.Fig. 4

Bottom Line: Low ER [Ca(2+)] has been reported to induce ER stress and activate the eIF2α/ATF4 pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles, CA, USA.

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.

Show MeSH
Related in: MedlinePlus