Survivin: Key Regulator of Mitosis and Apoptosis and Novel Target for Cancer Therapeutics

Abstract

Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of mitosis and programmed cell death. Initially, survivin was described as an inhibitor of caspase-9. However, over the last years, research studies have shown that the role of survivin in cancer pathogenesis is not limited to apoptosis inhibition but also involves the regulation of the mitotic spindle checkpoint and the promotion of angiogenesis and chemoresistance. Survivin gene expression is transcriptionally repressed by wild-type p53 and can be deregulated in cancer by several mechanisms, including gene amplification, hypomethylation, increased promoter activity, and loss of p53 function. This article reviews the multiple functions of survivin in the regulation of apoptosis, the promotion of tumorigenesis, and the development of survivin inhibitors as a novel anticancer therapeutic strategy.

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

“…Among the switched off genes, MMP-9 is involved in local invasion and metastasis (Takeuchi et al, 2004), being secreted by macrophages and tumor infiltrating lymphocytes, as well as by CRC cells (Ahmed et al, 2003). Survivin and c-myc are key regulators of cell growth in most human cancers and unfavorable prognostic markers, inhibiting cell death induced by several anticancer agents (Mita et al, 2008;Albihn et al, 2010). The epithelial cell adhesion molecule EpCAM is involved in a positive regulatory loop of Wnt signaling (Munz et al, 2009).…”

Embryonal neural tumours and cell death

“…Antagonising these caspases are a family of proteins called inhibitor of apoptosis proteins (IAPs) that block apoptosis by direct binding to caspases [30]. Currently there are nine known IAPs: X-linked IAP, cIAP1, cIAP2, melanoma IAP, neural apoptosis inhibitor protein, IAP-like protein 2, livin, apollon and survivin [31]. The functions of IAPs are in turn inhibited by endogenous antagonists like Smac/DIABLO, Omi/HtrA2 and XAF1.…”

“…The antiapoptotic mitochondria-associated proteins Bcl-2, Bcl-X L , Mcl-1 and survivin are all highly expressed in the developing neural tissue indicating that these proteins are important for the survival of progenitor cells [31,45,46]. Among these, myeloid cell leukaemia-1 (Mcl-1) has recently been shown to be absolutely required for neural precursor cell survival [46].…”

“…However, in cancer cells survivin expression has been shown to be deregulated by several mechanisms, including p53 mutation, amplification at the gene locus [60], demethylation of exons [65], increased promoter activity [64], or increased upstream signalling of PI3K/Akt or MAPK pathways [66]. Furthermore, the upregulation of survivin expression in cancer cells seems to be independent of the cell cycle, suggesting an enhancement of its anti-apoptotic role [31].…”

“…Several experimental therapeutic strategies have been developed to target survivin. These include targeting RNA expression, small molecule inhibitors of survivin function, or vaccination strategies to generate an antigen-specific immune response against survivin [31]. This latter strategy might prove efficient in neuroblastoma since children with high-risk neuroblastoma harbour robust cellular immune responses to survivin at the time of diagnosis [137].…”