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Boric acid activates PERK and ARE at physiological levels (372.2)
Author(s) -
Eckhert Curtis,
Yamada Kristin
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.372.2
Subject(s) - gclc , lncap , chemistry , prostate cancer , apoptosis , boric acid , cancer research , cancer , medicine , biochemistry , gene , organic chemistry , downregulation and upregulation
We first observed the chemopreventative nature of the plant nutrient boron as a significant association between intake and reduced risk of prostate cancer in the NHANES database and in cancer incidence across a groundwater boron gradient. Our observations have since been supported by others who showed boron intake is associated with reduced risk of lung cancer and cervical dysplasia, and lower prostate volume using ultrasound measurements. The underlying molecular mechanism involves the interaction of boric acid (BA) with cyclic ADP ribose with interruption of its endogenous Ca 2+ signaling function. One of the downstream modes of action is activation of ATF4 by phosphorylation of eIF2α. Our present objective was to test the hypothesis that physiological levels of BA increase phosphorylation through PERK. We tested this using MEF WT and MEF PERK ‐/‐ cells. Treatment of MEF WT cells with10 μM BA resulted in an increase in ph‐eIF2α/total eIF2α at 0.5‐1 hours. This increase was not observed in 10 μM BA treated MEF Perk ‐/‐ cells over a 6 hour time course. To further test the hypothesis that BA activates PERK, we measured Nrf2 activation, another PERK dependent pathway in DU‐145 cells. Nrf2 activation leads to translocation from the cytoplasm to the nucleus where it acts as a transcription factor for the antioxidant response element (ARE). Using immunofluorescence we showed treatment with 10 μM BA resulted in Nrf2 translocation to the nucleus at 2 hours. We measured mRNA levels of three ARE genes (HMOX‐1, NQO1, and GCLC) using real time PCR. 10 μM BA treatment resulted in an increase in mRNA levels of all three genes at 2 hours a result that is consistent with the temporal pattern of PERK activation and Nrf2 translocation to the nucleus. These results provide further definition to the underlying processes involved in boron chemoprevention.