Characterisation of the anti-apoptotic function of survivin-ΔEx3 during TNFα−mediated cell death

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-DEx3, is known to inhibit apoptosis, through undefined mechanisms. Here, we characterised these mechanisms upon TNFaÀmediated apoptosis, and showed that survivin-DEx3 acts as an adaptor, allowing the formation of a complex between Bcl-2 and activated caspase-3. The Bcl-2/survivin-DEx3 complex, but not survivin-DEx3 itself, inhibits the activity of caspase-3. Bcl-2 is therefore linked to the postmitochondrial apoptotic machinery by survivin-DEx3. Thus, survivin-DEx3 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-DEx3, rather than survivin alone, could be relevant for treating human cancers.

Significance of survivin, caspase-3, and VEGF expression in thyroid carcinoma

“…Moreover, it is known to be overexpressed and related with more aggressive behavior, increased tumor recurrence, chemotherapy resistance, increased survival in various tumors [3][4][5][6][10][11][12][13][14][15]. In TC, Haghpanah et al reported the significantly higher survivin expression in TC than in follicular adenoma, and Ito et al reported the significant link between survivin expression and the dedifferentiation of TC [16,17].…”

Alternative Splice Variants of Survivin as Potential Targets in Cancer

“…Survivin expression correlates with resistance to apoptosis induced by a number of chemotherapeutic agents [33,70,71] as well as death inducers such as Fas, TRAIL, TNF , etc [70][71][72][73][74][75][76][77]. Consistent with its anti-apoptotic role, Survivin localizes to the cytoplasm where it interacts with caspase 3 [70].…”

Significance of survivin expression: Prognostic value and survival in stage III non-small cell lung cancer

“…Survivin is a protein that is cell cycle-regulated with a robust increase in the G2/M phase in cancer cells (12,13). Survivin is known to be overexpressed and related with more aggressive behavior, increased tumor recurrence, chemotherapy resistance and increased survival in various tumors (6,(14)(15)(16)(17)(18)(19)(20)(21). As a prognostic factor, survivin expression is significantly associated with a poor clinical outcome in certain types of cancer, including liver (2), colorectal and breast (3,6).…”