Characterisation of the anti-apoptotic function of survivin-DeltaEx3 during TNFalpha-mediated cell death

• Published in: British journal of cancer Vol. 96; no. 11; pp. 1659 - 1666
• Main Authors: Malcles, M-H, Wang, H-W, Koumi, A, Tsai, Y-H, Yu, M, Godfrey, A, Boshoff, C
• Format: Journal Article
• Language: English
• Published: England 04-06-2007
• Subjects: Apoptosis - drug effects; Apoptosis - genetics; Caspase 3 - metabolism; Cell Death - drug effects; Cell Line, Tumor; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins - physiology; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Microtubule-Associated Proteins - physiology; Models, Biological; Models, Molecular; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Proteins - physiology; Protein Binding; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0007-0920

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-DeltaEx3, is known to inhibit apoptosis, through undefined mechanisms. Here, we characterised these mechanisms upon TNFalpha-mediated apoptosis, and showed that survivin-DeltaEx3 acts as an adaptor, allowing the formation of a complex between Bcl-2 and activated caspase-3. The Bcl-2/survivin-DeltaEx3 complex, but not survivin-DeltaEx3 itself, inhibits the activity of caspase-3. Bcl-2 is therefore linked to the postmitochondrial apoptotic machinery by survivin-DeltaEx3. Thus, survivin-DeltaEx3 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-DeltaEx3, rather than survivin alone, could be relevant for treating human cancers.