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Recently, a select number of viral and cellular proteins sharing a unique property have been identified, namely apoptin, HAMLET, TRAIL, MDA7, E4ORF4, NS1 and Brevinin-2R, where all have the remarkable ability to selectively kill transformed and/or tumour cells, while causing no or only minor cytotoxicity in normal and non-transformed cells. Research worldwide is now starting to unravel the molecular signalling pathways by which each of these proteins exerts its tumour-selective function, and the first (pre)clinical studies are very promising. The workshop ‘Proteins Killing Tumour Cells’ brought together, for the first time, researchers working on this novel class of intriguing proteins. Participants from 14 different countries shared their views on (possible common) mechanisms behind tumour-specific apoptosis induction and strategies to implement this knowledge in the clinic. The ability of certain viral and cellular proteins to induce tumour-selective apoptosis implies the existence of a common set of characteristics, shared by all tumour cells, and recognized by these tumour-killing proteins (see Table 1). Mathieu Noteborn highlighted the delicate balance between survival and death pathways in normal and transformed cells, thereby effectively setting the theme of the meeting. Michael Green (University of Massachusetts, USA), using a genome-wide RNA interference screen, implicated secreted IGFBP7 (insulin-like growth factor binding protein 7) in the induction of senescence and apoptosis by oncogenic Braf. Paradoxically, overexpressing both proteins in normal melanocytes induced senescence, whereas in melanoma cells this resulted in apoptosis. James Pipas (University of Pittsburgh, USA) discussed the role of different domains of the SV40 large T antigen in oncogenic transformation. For instance, the N-terminal J-domain, in combination with the LXCXE domain, induces cellular proliferation by inactivating Rb and liberating E2Fs from repression. Additionally, microarray analysis revealed a new ‘detoxification’ function for the C-terminal domain of the large T antigen via the p450 pathway. Jason Arroyo from the Hahn group (Dana Farber Cancer Institute, USA) explained how the SV40 small T antigen contributes to the induction of transformation by inhibiting the protein phosphatase 2A (PP2A) family. Specific subunits of these heterotrimeric proteins are implicated in cell transformation: RNAi knockdown of the B56γ-subunit and mutation of the Aβ-subunit both promote transformation, whereas deletion of the Aα-subunit results in apoptosis. A common target of both transforming and tumour-selective apoptosis-inducing viral proteins appears to be the anaphase-promoting complex (APC). As illustrated by Jose Teodoro (McGill University, Canada), knockdown of the APC1 subunit by siRNA resulted in G2M cell cycle arrest and apoptosis in human tumour cells. Strikingly, this effect is mimicked by APC inactivation through interaction with either apoptin or adenovirus E4orF4, two proteins discussed during this meeting, thus revealing a common pathway. Apoptin's tumour-selective cytotoxicity appears to be associated with nuclear localization and phosphorylation on T108. The nuclear targeting signal within apoptin comprises a bipartite nuclear import signal flanking a nuclear export signal. David Jans (Monash University, Australia) proposed a model where, selectively in cancer cells, NES function is inhibited by phosphorylation of apoptin on Thr108, resulting in nuclear accumulation. Dong-Jun Peng (Huazhong University, China) showed, in collaboration with the Leiden group, that transient expression in normal fibroblasts of the SV40 large/small T antigens is sufficient to induce apoptin's nuclear localization, phosphorylation and apoptosis. Interestingly, suppression of PP2A activity by the small T antigen (see Arroyo, above) appears to play a major role in this process. Paola Bruno from the Tavassoli group pointed out that low levels of apoptin phosphorylation can be detected in normal early passage fibroblasts infected with adenovirus expressing apoptin fused to GFP. Apparently, apoptin kinase activity is present in normal cells but has very low activity, whereas in tumour cells it is highly activated. Rhyenne Zimmerman introduced a number of apoptin-interacting partners (AIPs) identified by the yeast two-hybrid technique. Strikingly, these AIPs are all known or putative tumour-suppressor genes or oncogenes, likely to be implicated in the differential behaviour of apoptin in normal and cancer cells. Poramaporn Klanrit showed for the first time (in collaboration with the Melino group (University of Rome, Italy) that apoptin is able to activate TAp73 and its downstream pro-apoptotic target PUMA, independently of p53 function. Joseph Cheng from the Norris group (University of South Carolina, USA), reported on the implication of the ceramide pathway in the tumour-selective activity of apoptin. In prostate cancer cells, apoptin expression results in ceramide upregulation and acid ceramidase inhibitors can significantly enhance apoptin cytotoxicity both in prostate cancer cell lines and tumour xenografts. Several groups discussed the use of a protein transduction strategy to deliver apoptin via the TAT protein transduction domain from HIV-1. Joop Gäken (King's College London, UK) investigated the potential of transduced apoptin to purge haemopoietic stem cells of malignant leukaemia cells, for use in autologous transplantation. His-tagged TAT-apoptin protein was shown to induce apoptosis in leukaemic cells but not in normal blood lymphocytes. Marcella Flinterman presented a novel mammalian secretable delivery system, using a modified TAT-tag. Jun Sun (Huazhong University, China) reported topical application of PTD4-apoptin onto the tumour bearing skin of immune-deficient mice. Apoptosis and disruption of the tumour integrity were apparent, whereas the surrounding normal tissue was not affected. Apoptin, E4ORF4, NS1, HAMLET, TRAIL, MDA7 and Brevinin-2R are part of a new family of proteins, consisting of both cellular and viral proteins that use various mechanisms of cell death, but share one key feature: their killing activity is efficient in transformed and cancer cells and negligible in normal and healthy cells. A potential new member of this tumour killing protein family, IGFBP7, was introduced during the meeting. Besides the obvious applications for tumour targeting, these proteins also constitute very sensitive probes to zoom-in onto essential molecular and cellular changes during carcinogenic transformation. The workshop was unanimously assessed as very stimulating, bringing together for the first time various research groups working on different proteins but all with similar potentials for cancer therapeutics. As one participant stated: ‘We all thought we were orphans, but now we know we are family’.

Family at last: highlights of the first international meeting on proteins killing tumour cells