Boric Acid Causes ER Stress and Activates the eIF2alpha/ATF4 and ATF6 Branches of the Unfolded Protein Response in Prostate Cancer Cells and Using Toxicology in the Public Interest

摘要: Author(s): Kobylewski, Sarah Ellen | Advisor(s): Eckhert, Curtis D. Abstract: Nutritional chemoprevention is a growing area in the field of toxicology. What we do and not eat has major impact on development cancer. However, it difficult to show causal relationship between natural product cancer prevention because mechanistic biochemical data are often missing animals studies can be inconclusive. Both determining elucidating molecular mechanisms that modulate pathological endpoints necessary components risk assessment process used determine if chemicals properties laboratory safe for public use. The research presented this dissertation focuses through consumption nutrient or avoidance toxic food additives. Part I presents elucidated pathway activated by boric acid (BA), an essential plant nutrient, which may provide insight into inhibition cell proliferation prostate cells reduced II consists toxicology application interest health. It critical analysis two commonly consumed FDA-approved additives, rebaudioside A, artificial sweetener, dyes. In I, was shown BA isoform-specific antagonist ryanodine receptor (RyR), calcium (Ca2+) channel, but RyR functions interacting competing with receptor's only known endogenous agonist. This results altered Ca2+ signaling induces ER stress eIF2alpha/ATF4 ATF6 branches unfolded protein response (UPR) DU-145 cells. UPR tightly associated proliferation. specific have BA-treated correlated survival II, describe how vivo vitro A dyes demonstrated their toxicity. showed they present increased health important given widespread use public. here thus both sides