The role of endoplasmic reticulum (ER) stress in mediating the apoptotic effect of selenium compounds

Converging data from epidemiological, ecological, and clinical studies have shown that selenium (Se) can decrease the risk for some types of human cancers. Mechanisms of the anti-cancer action of Se compounds are not fully understood; however, several have been proposed, which include the induction of cell apoptosis, inhibition of cell proliferation, modulation of the redox state, detoxification of carcinogen, stimulation of the immune system, and inhibition of angiogenesis. Among these potential mechanisms of Se action, the induction of apoptosis is considered an important cellular event that can account for the cancer preventive eff ects of Se. Prior to the occurrence of apoptosis, the accumulation of aberrantly folded proteins in the endoplasmic reticulum (ER) triggers a defined set of transducers to correct the defects or commit the cells to apoptosis if the rescue eff ort is exhausted. Se compounds alter the expression and/or activities of ER stress-associated and mitochondria-associated signaling molecules. Mechanistic studies have demonstrated that the methylselenol metabolite pool has many desirable attributes of chemoprevention, whereas the hydrogen selenide pool with excess selenoprotein synthesis can lead to DNA single-strand breaks. This ambiguity is due to several factors, including the chemical nature of Se compounds (inorganic vs. organic) and their intracellular metabolism, the type of experimental model, and the dose used. This chapter focuses on elucidation of the molecular mechanisms of cancer prevention by Se with the apoptotic events via the ER stress response.