| Boric acid (BA) intake reduces the risk of prostate and lung cancer and inhibits prostate cancer cell proliferation. Despite its clear anticancer effects, little is known about BA's localization, mode, or mechanism of action in human cells. We used nano scale imaging secondary ion mass spectrometry to determine BA localization and found that it localizes in distinct locations in the cytoplasm, surrounding the nucleus. We also show that physiological levels of BA induced endoplasmic reticulum (ER) stress as indicated by ER swelling and vacuolization and differentially activates the unfolded protein response (UPR). Phosphorylation of eif2alpha increased and cell survival proteins associated with the UPR (ATF4 and Bip) are up regulated white apoptosis related proteins (GADD153/CHOP and GADD34) are down regulated. Transcription factors ATF6 and XBP1 are not activated by BA treatment. Low doses of BA inhibit the release of ryanodine receptor (RyR), inositol 1,4,5-trisphosphate receptor (IP3R), and thapsigargin sensitive Ca2+ stores and lowers resting luminal Ca2+ levels by 30%. BA has a lower potency, yet similar efficacy in the less aggressive LNCaP prostate cancer cell line and the non-tumor prostate cell line, PWR1E. We believe that by blocking stored Ca2+ release, BA also inhibits capacitative calcium entry (CCE), which is essential for cell proliferation. This results in inhibition of proliferation but not cell death due to the activation of the UPR survival pathway. This work has made great strides in elucidating BA's mode of action. It may have broader applicability in such areas as diabetes and protection of tissues during ischemia/reperfusion injury due to the preferential activation of adaptive UPR. Overall, it is important to understand how BA works in reducing prostate cancer risk because of its low toxicity and promising use as a safe and effect preventative measure and treatment alternative for prostate cancer patients as well as potential applications in other diseases. |
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