1. ¹Cancer Research UK Viral Oncology Group, Wolfson Institute for Biomedical Research, University College, London, UK
2. ²Institute of Microbiology and Immunology, National Yang-Ming University, Taiwan
3. ³Department of Education and Research, Taipei City Hospital, Taiwan

Correspondence: C Boshoff, Wolfson Institute for Biomedical Research, Cruciform Building, Gower Street, University College London, London WC1E 6BT, UK. E-mail: c.boshoff@ucl.ac.uk

⁴These authors contributed equally to this work.

Received 25 January 2007; Revised 2 April 2007; Accepted 2 April 2007; Published online 15 May 2007.

Abstract

Survivin is an oncogenic protein involved in cell division and acts as an anti-apoptotic factor. It is highly expressed in most cancers and is associated with chemotherapy resistance, increased tumour recurrence, and shorter patient survival. This makes anti-survivin therapy an attractive cancer treatment strategy. These functions are mediated by several survivin spliced variants, whose expression may correlate with cancer progression. One of the spliced variants, survivin-Ex3, is known to inhibit apoptosis, through undefined mechanisms. Here, we characterised these mechanisms upon TNF-mediated apoptosis, and showed that survivin-Ex3 acts as an adaptor, allowing the formation of a complex between Bcl-2 and activated caspase-3. The Bcl-2/survivin-Ex3 complex, but not survivin-Ex3 itself, inhibits the activity of caspase-3. Bcl-2 is therefore linked to the postmitochondrial apoptotic machinery by survivin-Ex3. Thus, survivin-Ex3 plays a key role in the inhibition of caspase-3 activity, and in the control of the mitochondrial checkpoint of apoptosis. This study suggests that targeting survivin-Ex3, rather than survivin alone, could be relevant for treating human cancers.