Role of the XIAP-Copper Axis in Prostate Cancer

: We have identified, confirmed, and characterized a novel functional and physical interaction between the X-linked inhibitor of apoptosis (XIAP) and the copper chaperone for superoxide dismutase (CCS). We performed a targeted genetic screen in yeast to identify proteins involved in delivery of copper (Cu) to XIAP. This screen identified CCS as a primary mediator of Cu delivery to XIAP in yeast, and we subsequently determined that CCS delivers Cu to XIAP in mammalian cells as well. In addition, XIAP targets CCS for ubiquitination through its E3 ubiquitin ligase activity. This ubiquitination event seems to be proteasome-independent and leads to enhancement of CCS activity rather than CCS degradation. Taken together, our results have shed substantial light on the interplay between XIAP and copper homeostasis. These studies have the potential to significantly improve our understanding of not only prostate cancer but also other disorders in which XIAP or Cu metabolism is deregulated. This work was published in April 2010 and presented at IMPaCT 2011 in March 2011.