Joint Annual Research Report 2004 - The Royal Marsden

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(a) (b) Caspase inactive DIAP1 IAP-antagonist DIAP1 Figure 1. Regulation of apoptosis by IAPs and IAP-antagonists. (a) IAPs suppress apoptosis by directly binding to caspases, thereby obstructing the caspases access to their substrates. IAPs block caspases by binding to caspases and targeting them for ubiquitylation. (b) In cells that are destined to die, levels of IAP-antagonists become elevated. Cell death is induced when IAPantagonists bind to IAPs, whereby caspases are displaced and liberated from IAP complexes. observed in non-small cell lung cancer cells. Moreover, chromosomal translocations of cIAP1 are frequently found in mucosal-associated lymphoid tissue (MALT) lymphomas, while Livin/ML-IAP/KIAP is highly expressed in melanomas. Caspase active DIAP1 DIAP1 Caspase active and unguarded DIAP1 Ubiquitylation Degradation Substrate intact DIAP1 Degradation Substrate cleaved Proteasome Survival Proteasome Cell death The observation that IAPs suppress apoptosis very effectively and are present in cancer cells strongly suggests that IAP-mediated inhibition of apoptosis contributes to tumour pathogenesis, disease progression and/or resistance to drug treatment. Mark Ditzel and Rebecca Wilson have investigated how IAPs suppress cell death. They made the striking observation that IAPs inhibit deadly caspases by fusing another protein, called ubiquitin, onto caspases (Figure 1). The ubiquitin label inactivates the caspases and the cell survives. The fate of proteins that are modified with a ubiquitin label can vary substantially, with some polyubiquitylated proteins being disassembled and destroyed by the cell’s demolition centre, the proteasome, while others end up in different subcellular compartments, and yet others are inactivated. IAPs belong to a specialised group of proteins, called E3 ubiquitin protein ligases, which transfer ubiquitin protein labels onto caspases thereby blocking cell death. Survival through mutual annihilation While IAPs label caspases with ubiquitin, caspases are not the only proteins that are modified with ubiquitin. Mark Ditzel and Rebecca Wilson also found that, in the process, IAPs themselves become coated with ubiquitin. Attaching ubiquitin to IAPs has dire consequences for the affected IAP itself, since this modification targets it for proteasomal demolition. Because IAPs represent the last line of defence against caspase-mediated damage it appears to be somewhat counterintuitive that the cell gets rid of its own guardian. So, why should it be beneficial to a cell to destroy its own protector The answer to this is that ubiquitin-mediated instability of IAPs reflects the natural occupational hazard of being a ubiquitin-handling E3 protein ligase. The intrinsic instability of IAPs and their anti-apoptotic activity is intimately intertwined. Genetic and molecular studies indicate that IAP destruction is in fact essential for their ability to block apoptosis. Only IAPs that are unstable and are destroyed are capable of controlling caspases. This raises the intriguing possibility that IAPs suppress apoptosis by actively searching out and destroying activated caspases. In this respect, IAPs and caspases would be coordinately destroyed in an altruistic sacrifice. This discovery has major implications for the generation of novel therapeutic small molecule inhibitors designed to block the E3 ubiquitin protein ligase activity of IAPs. In the presence of such inhibitors of IAPs, caspases would no longer be coated with ubiquitin and hence would remain active and destroy the cancer cell. Since only cancer cells, but not normal cells, constantly drive the activation of caspases, such E3- inhibition is predicted to selectively kill tumour cells.
CANCER BIOLOGY SMAC ’em dead It is now clear that apoptosis is implemented by caspases. To date 11 caspases have been identified in humans. While XIAP suppresses only three of these, it is currently unclear how the remaining set of caspases is controlled. How caspases are kept quiet Tencho Tenev and Anna Zachariou have studied how caspases are kept in abeyance. They made the discovery that certain caspases carry an evolutionarily conserved motif, which is designed to attract and bind to IAPs, hence the name IAP-binding motif (IBM). Normally, this IBM is buried deep within a dormant, non-active caspase. However, when the caspase is activated, this motif is exposed and acts like a magnet for IAPs. Thus, even when caspases are activated this will not necessarily end in cell death, because IAPs can home in on active caspases and smother their destructive potential. The most exciting aspect of this discovery is that only a tiny motif, in fact, one single amino acid residue of the caspase, is crucially involved in anchoring it to IAPs. Mutation of this one residue completely abrogates the interaction between IAPs and caspases. Consequently, activated caspases become invisible for IAPs and therefore are unrestrained and free to cause mayhem. The IAP: caspase complex – a new pharmaceutical target The fact that such a tiny motif is important for the caspase:IAP association makes it an exciting pharmaceutical target. Indeed, preliminary studies using small molecule chemotherapeutic inhibitors that mimic this single amino acid residue have already given rise to very exciting preliminary results. Numerous cancer cell lines appear to be exquisitely sensitive to such agents. Cancer cells that have been treated with such IBM mimetics appear to keel over and die owing to spontaneous and unrestrained activation of caspases. The agents break up the IAP:caspase complex thereby liberating caspases from IAP-mediated inhibition. Another regulator of IAPs is a protein called SMAC which activates caspases by directly inhibiting IAPs. SMAC mimetics are being developed as anticancer agents acting through promoting apoptosis. SMAC mimetics seem not to harm normal cells, yet selectively destroy cancer cells. This selectivity strongly indicates that cancer cells are particularly addicted to IAPs for their survival. Breaching the barricade This SMAC strategy to kill cancer cells is not a novel man-made creation but actually is a strategy that nature has evolved to kill cells during the normal sculpting of the human body. Normal cells that are destined to die overcome the IAP-mediated roadblock on caspases. A specialised group of naturally occurring killer proteins (IAP-antagonists) trigger cell death by directly blocking the access of IAPs to caspases. The sole function of these assassin proteins is to bind and antagonise IAPs thereby displacing and liberating caspases (see Figure 1). Once displaced and relieved of IAP-mediated inhibition, caspases effect apoptosis. In the fruit fly Drosophila melanogaster, the world’s best-known model organism, the activity of IAPantagonists – which carry intriguing names such as Reaper, Grim, Sickle, Hid and Jafrac2, is essential for apoptosis during development. Cells that lack Reaper, Grim and Hid completely fail to activate the apoptosis programme – just like cancer cells. Prospects for the future Small molecule inhibitors already exist to block IAPs. Future studies will undoubtedly determine whether such SMAC compounds can be turned into efficacious small molecules that enhance the apoptotic mechanism, either alone or in combination with conventional chemotherapeutic agents. 23
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