Science, Technology and Engineering

Silke Laboratory

Department of Biochemistry

Research - Inhibitor of Apoptosis Proteins and Cancer

Apoptosis or programmed cell death is a physiological process for killing cells and is critical for the normal development and function of multicellular organisms. Apoptosis is fundamentally important in preventing tumourigenesis and it is now widely acknowledged that defects in the apoptotic pathway result in increased tumour formation, with one of the seminal papers in the field coming from Australia (Fig.1, (Strasser et al., 1990).

Figure 1 Over-expression of an oncogene (eg Myc) results in tumour formation and death, co-expression of an anti-apoptotic protein (Bcl2) significantly increases tumour formation and the ensuing lethality.

The effectors of the cell death program are enzymes called caspases, that degrade essential proteins within the cell and effectively digest the cell from the inside. Caspases can be regulated directly or indirectly by the so called Inhibitor of apoptosis proteins or IAPs. It has been shown that some tumour types, such as hepatocarcinoma are frequently associated with amplification of cIAP1 and that the tumour cells require cIAP1 to progress to full blown tumours (Zender et al., 2006).

The discovery of natural mammalian IAP antagonists by (Verhagen et al., 2000; Du et al., 2000) and their mode of action led directly to the development of IAP targeting drugs that mimicked the action of the natural IAP antagonists. Our lab has been fortunate to collaborate with one of the companies involved in the development of such drugs; Tetralogic Pharmaceuticals, . Together with Tetralogic Pharmaceuticals our lab has recently described how these novel compounds are able to kill cancer cells and this exciting work was published in the prestigious Journal Cell (Vince et al., 2007).

One particularly exciting aspect of these drugs is that they specifically target cancer cells but leave normal cells relatively unaffected and we are focused on trying to discover why the drugs are so selective with the aim of further improving the utility of these new drugs.

Our lab collaborates with many other international groups including, Dr Catherine Day's group, , Dr Pascal Meier's group and Dr Paul Ekert's group, , Dr Robert Brink's lab , all using different approaches with the ultimate aim of discovering how IAPs function and how that knowledge might be applied to deliver better anti-cancer drugs to the clinic.

Du, C., Fang, M., Li, Y., Li, L., and Wang, X. (2000). Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition. Cell 102, 33-42.

Strasser, A., Harris, A.W., Bath, M.L., and Cory, S. (1990). Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331-33.

Verhagen, A.M., Ekert, P.G., Pakusch, M., Silke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J., and Vaux, D.L. (2000). Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins. Cell 102, 42-53.

Vince, J.E., Wong, W.W., Khan, N., Feltham, R., Chau, D., Ahmed, A.U., Benetatos, C.A., Chunduru, S.K., Condon, S.M., et al. (2007). IAP Antagonists Target cIAP1 to Induce TNFalpha-Dependent Apoptosis. Cell 131, 682-693.

Zender, L., Spector, M.S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.T., Luk, J.M., Wigler, M., et al. (2006). Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253-267.