Peering down the kaleidoscope of thiol proteomics and unfolded protein response in studying the anticancer action of selenium

Abstract

A monomethylated selenium metabolite called methylseleninic acid (MSA) has recently been shown to cause global thiol redox modification of proteins. These changes represent a form of cellular stress due to protein misfolding or unfolding. When this occurs in the endoplasmic reticulum (ER), a process known as unfolded protein response (UPR) is orchestrated to repair the damage or commit the cells to apoptosis if the rescue effort becomes inadequate. Treatment of PC-3 human prostate cancer cells with MSA leads to activation of three signature ER stress transducers and increased expression of UPR target genes, as exemplified by GRP78 and GADD153. GRP78 is part of the damage control mechanism, while GADD153 is a transcription factor associated with growth arrest and apoptosis. Transfection with GRP78 largely negates the apoptotic effect of MSA and GADD 153 induction because an abundance of GRP78 allows cells to cope better with ER stress. Conversely, knocking down GRP78 by siRNA magnifies the cell growth arrest effect of MSA and GADD153 expression. Collectively, the research findings support the idea that UPR plays an important role in mediating the anticancer activities of selenium.