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

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