SIAH1-induced p34(SEI-1) polyubiquitination/degradation mediates p53 preferential vitamin C cytotoxicity

Abstract

Vitamin C is considered as an important anticancer therapeutic agent although this view is debatable. In this study, we introduce a physiological mechanism demonstrating how vitamin C exerts anticancer activity that induces cell cycle arrest and apoptosis. Our previous and current data reveal that p53 tumor suppressor is the prerequisite factor for stronger anticancer effects of vitamin C. In addition, vitamin C-mediated cancer cell cytotoxicity appears to be achieved at least partly through the downregulation of the p34(SEI-1) oncoprotein. Our previous study showed that p34(SEI-1) increases the survival of various types of cancer cells by inhibiting their apoptosis. Present data suggest that vitamin C treatment decreases the p34(SEI-1) expression at the protein level and therefore alleviates its anti-apoptotic activity. Of note, SIAH1, E3 ubiquitin ligase, appears to be responsible for the p34(SEI-1) polyubiquitination and its subsequent degradation, which is dependent on p53. In summary, vitamin C increases cancer cell death by inducing SIAHl-mediated polyubiquitination/degradation of the p34(SEI-1) oncoprotein in a p53-dependent manner.