Survivin - an inhibitor of apoptosis that drives tumorigenesis and metastasis

Mon, 07/06/2015 - 14:30

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Apoptosis is the tightly regulated process of programmed cell death. It plays an important role in normal physiologic development but has also been implicated in a number of diseases. Apoptosis is constantly downregulated by a family of anti-apoptotic proteins known as the inhibitors of apoptosis proteins (IAP). Every member of the IAP family contains one to three copies of a baculovirus IAP repeat (BIR domain). The BIR domain is a zinc-binding motif that allows these proteins to interact with and inhibit the pro-apoptotic caspases. One of the more recently characterized members of this family is Survivin, a 16.5 kDa protein, the smallest in the family. Survivin is unique in that it contains only one BIR domain and homodimerizes with itself before interacting with a caspase. Survivin plays a critical role in fetal development but is undetectable in healthy adult tissues. Ectopic expression of Survivin has been identified in a number of malignancies. Expression of Survivin drives cancer cell survival, proliferation, and metastasis.

Xu et. al. identified a mutation in the promoter region of Survivin which is responsible for its ectopic expression (1). The group identified several polymorphisms in the promoter region and correlated these to protein levels using western blot and the Survivin antibody. The most commonly identified mutation among was in the CDE/CHR repressor domain. This mutation prevents the normal physiologic repression of Survivin, explaining its ectopic expression in many cancers.

Survivin has also been identified as a prognostic marker in a number of malignancies. Augello et. al. used the Survivin antibody to correlate Survivin levels to overall prognosis in hepatocellular carcinoma (HCC) (2). This group used the Survivin antibody to perform immunohistochemistry on tissue samples from 69 HCC patients and matched these findings to follow-up survival data. The group found that overexpression of Survivin correlated with advanced stage tumors and poor prognosis. Meanwhile, Vischioni et. al. found that Survivin localization could be used as a prognostic factor in NSCLC (3). The group used the Survivin antibody to assess Survivin levels and cellular localization in 53 NSCLC tumor samples. In this study, nuclear localization of Survivin correlated with longer overall and relapse-free survival.

Given Survivin’s role in tumorigenesis, Ruckert et. al. sought to understand how inhibition of Survivin might re-sensitize pancreatic cancer cells to apoptosis (4). The group used simultaneous gene silencing of Survivin, XIAP, and Bcl-2 via siRNA knockouts. The group confirmed their knockouts using the Survivin antibody and antibodies against XIAP and Bcl-2. Apoptosis induction in the triple knockout cells was measured by flow cytometry and was significantly higher than the control or any single knockout. Apoptosis resistance is a hallmark of many cancers, and Survivin is considered promising therapeutic target.
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  1. 15383173
  2. 19397802
  3. 15520067
  4. 20646298

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