Smac’d to Death
Authors: Foley John F. 
Published: December 2007

Inhibitor of apoptosis (IAP) proteins bind, through their baculovirus IAP repeat (BIR) domains, to caspases, the proteases that mediate apoptosis, thus preventing apoptotic cell death. IAPs also contain RING domains and so act as E3 ubiquitin ligases that target proteins (and themselves) for proteasomal degradation. IAPs are more abundant in cancer cells than in normal cells, making IAPs attractive therapeutic targets. IAP activity is blocked by Smac (second mitochondrial activator of caspases), whose release from mitochondria is triggered by proapoptotic stimuli. Two groups have now designed and characterized mimetics of Smac. Varfolomeev
et al
. treated various cancer cell lines with their compounds, MV1 and BV6, and saw the rapid degradation of the IAP family members, c-IAP1 and c-IAP2, as assessed by Western blotting, which was blocked by an inhibitor of the proteasome. Both compounds also led to a dose-dependent increase in cell death, which was blocked by the caspase inhibitor z-VAD. Blockade of tumor necrosis factor-α (TNF-α) inhibited BV6-mediated apoptosis, as did a small interfering (si) RNA against the TNF-α receptor (TNFR1). Vince
et al
. found similar results when characterizing their IAP antagonist compounds. TNF-α production is characteristic of nuclear factor κB (NF-κB) activation. Both groups showed that the canonical and noncanonical NF-κB pathways were activated in cells in which IAPs were antagonized. NIK (NF-κB-inducing kinase), an activator of the noncanonical pathway, was constitutively bound to IAPs and then degraded, which was prevented by treatment with the Smac mimetics. Apoptosis mediated by these compounds was blocked by inhibitors of NF-κB. IAP antagonism also increased the recruitment to the TNFR1 of the kinase receptor-interacting protein 1 (RIP1), which is important for canonical NF-κB activation. Together these studies show that rather than simply interfering with the ability of IAPs to bind to caspases, Smac mimetics trigger IAP degradation, which has a twofold outcome. First, caspases are now uninhibited and responsive to a proapoptotic signal. Second, IAP degradation removes a block to noncanonical NF-κB activation, leading to the production of TNF-α that acts in an autocrine fashion to trigger cell death. Wu
et al
. discuss the potential use of these compounds in anticancer therapies.

E. Varfolomeev, J. W. Blankenship, S. M. Wayson, A. V. Fedorova, N. Kayagaki, P. Garg, K. Zobel, J. N. Dynek, L. O. Elliott, H. J. A. Wallweber, J. A. Flygare, W. J. Fairbrother, K. Deshayes, V. M. Dixit, D. Vucic, IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis.
Cell
131
, 669-681 (2007).
[Online Journal]

J. E. Vince, W. W.-L. Wong, N. Khan, R. Feltham, D. Chau, A. U. Ahmed, C. A. Benetatos, S. K. Chunduru, S. M. Condon, M. McKinlay, R. Brink, M. Leverkus, V. Tergaonkar, P. Schneider, B. A. Callus, F. Koentgen, D. L. Vaux, J. Silke, IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis.
Cell
131
, 682-693 (2007).
[Online Journal]

H. Wu, J. Tschopp, S.-C. Lin, Smac mimetics and TNFα: A dangerous liaison?
Cell
131
, 655-658 (2007).
[Online Journal]