Smac Mimetics and TNFα: A Dangerous Liaison?

Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. It has been thought that small-molecule mimetics of Smac, an endogenous IAP antagonist, might potentiate apoptosis in cancer cells by promoting caspase activation. However, three recent papers, two in Cell () and one in Cancer Cell (), now report that Smac mimetics primarily kill cancer cells via a different mechanism, the induction of autoubiquitination and degradation of cIAPs, which culminates in TNFα-mediated cell death.