Compounds that activate or mimic the pro-apoptotic protein SMAC (second mitochondrial-derived activator of caspase) cause regression of human lung cancer xenografts by increasing apoptotic signaling through tumor necrosis factor receptor 1 (TNFR1).
The capacity to specifically induce apoptosis in cancer cells by manipulating components of the apoptotic pathway has been a goal since this pathway was first described. Three recently published papers now indicate the mechanism through which one of the new apoptosis-based therapies — the inhibitor of apoptosis protein (IAP) antagonists (SMAC mimetics) — function to induce cell death in susceptible cancer cells.
BANANASTOCK
SMAC (also known as DIABLO) is a protein that is released from the mitochondria during apoptosis and binds a family of anti-apoptotic proteins — IAPs. IAP expression levels are increased in a number of human tumours, so compounds that mimic SMAC have been developed. Some tumour cell lines have shown sensitivity to these compounds in vitro, but others have not. So what determines this?
John Silke and colleagues, using an IAP inhibitor that was developed on the basis of the crystal structure of the interaction of SMAC with the BIR3 domain of X-linked IAP (XIAP, also known as BIRC4), and Vishva Dixit, Domagoj Vucic and colleagues, using monovalent and bivalent IAP antagonists that were designed using a structure-based approach, found that their compounds induce sensitive cells to secrete tumour necrosis factor (TNF), triggering apoptosis through an autocrine pathway. Both groups showed that their IAP antagonists induced the degradation of cIAP1 (also known as BIRC2) (and cIAP2 (also known as BIRC3) in the case of Dixit and colleagues) through a proteasome-dependent mechanism. Antagonism of cIAP1 also enables the binding of receptor-interacting serine/threonine kinase 1 (RIPK1) to TNF receptor 1 (TNFR1) and this induces activation of the canonical nuclear factor B (NFB) pathway and, through stabilizing NFB-inducing kinase (NIK, also known as MAP3K14), the non-canonical NFB pathway. These pathways are activated in cell lines regardless of whether the cells are induced to die by the IAP antagonists. In sensitive cells however, activation of NFB induces the secretion of TNF. Furthermore, the degradation of cIAP1 seems to be crucial for cell killing by TNF because loss of cIAP1 increases apoptotic signalling through TNFR1.
Xiaodong Wang and colleagues had previously shown that their SMAC mimetic, which is designed to resemble the amino-terminal amino acids of SMAC that interact with the BIR3 domain of XIAP, binds IAPs and thus sensitizes cells to exogenous TNF-induced apoptosis. Now they have found that the few human lung cancer cell lines that are sensitive to a SMAC mimetic alone are responsive because they secrete TNF, resulting in the engagement of TNFR1 and subsequent activation of caspase 8 through a death-inducing complex that includes RIPK1. Importantly, however, Wang and colleagues also showed that, as a single agent, their SMAC mimetic can induce regression of sensitive human lung cancer xenografts, with 40% of treated animals remaining free of tumours. Therefore, in specific tumours a SMAC mimetic could be efficacious without the need for combined chemotherapy. In addition, in agreement with their previous findings and the other two groups, some cells that did not secrete TNF were sensitive to a combination of both the SMAC mimetic and exogenous TNF.
These findings are concurrent with mutations present in human tumours. For example, patients with multiple myeloma that have inactivating mutations in both cIAP1 and cIAP2 have constitutive activation of the non-canonical NFB pathway, and other cancer types show increased expression of cIAP1 that might suppress TNF-mediated apoptosis. In theory, such tumours should respond to treatment with a SMAC mimetic; however, further work is needed to fully characterize the factors that make a cell sensitive to these agents.
Nicola McCarthy
References
Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNF dependent apoptosis. Cell131, 682–693 (2007) | Article | PubMed |
Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of cIAPs, NFB activation and TNF-dependent apoptosis. Cell131, 669–681 (2007) | Article | PubMed |
Petersen, S. L. et al. Autocrine TNF signaling renders human cancer cells susceptible to Smac-mimetic induced apoptosis. Cancer Cell12, 445–456 (2007) | Article | PubMed |
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