SUMOylation is widely reported as a cytoprotective response against cell stress induced by ischemia and reperfusion. However, it is still unclear what other cell stressors trigger protein SUMOylation, what mechanisms enhance and maintain the enhanced SUMOylation, and if it is a general protective mediator against other cytotoxic stresses, toxic heavy metal cadmium for instance. Here, we show increased levels of SUMOylation and decreased levels of the deSUMOylation enzyme SENP3 in PC12 cells exposed to CdCl2. In addition, SENP3 knockdown reduced cadmium-induced apoptosis and cell death in PC12 cells, while SENP3 overexpression enhanced cell death. These results suggest that SENP3 is an important regulator of the cell response to cadmium stress. Our finding is consistent with previous reports of SENP3 and SUMOylation in ischemia, and implies that the regulation of SENP3 levels and subsequent changes in SUMOylation could be a general cytoprotective mechanism.