Trace of survivin in cancer Fereshteh Shojaei a , Farshad Yazdani-Nafchi a , Mehdi Banitalebi-Dehkordi a , Mohammad Chehelgerdi a and Milad Khorramian-Ghahfarokhi b Survivin is one of the most cancer-specific proteins overexpressed in almost all malignancies, but is nearly undetectable in most normal tissues in adults. Functionally, as a member of the inhibitor of apoptosis family, survivin has been shown to inhibit apoptosis and increase proliferation. The antiapoptotic function of survivin seems to be related to its ability to inhibit caspases directly or indirectly. Furthermore, the role of survivin in cell cycle division control is related to its role in the chromosomal passenger complex. Consistent with its determining role in these processes, survivin plays a crucial role in cancer progression and cancer cell resistance to anticancer drugs and ionizing radiation. On the basis of these findings, recently survivin has been investigated intensively as an ideal tumor biomarker. Thus, multiple molecular approaches such as use of the RNA interfering technique, antisense oligonucleotides, ribozyme, and small molecule inhibitors have been used to downregulate survivin regulation and inhibit its biological function consequently. In this review, all these approaches are explained and other compounds that induced apoptosis in different cell lines through survivin inhibition are also reported. European Journal of Cancer Prevention 00:000–000 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. European Journal of Cancer Prevention 2018, 00:000–000 Keywords: cancer, chromosomal passenger complex, inhibitor of apoptosis family, survivin a Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord and b Department of Pathobiology, School of Veterinary Medicine, Division of Biotechnology, Shiraz University, Shiraz, Iran Correspondence to Mohammad Chehelgerdi, PhD, Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran Tel: +98 910 177 1579; e-mail: chehelgerdi1992@gmail.com Received 26 February 2018 Accepted 18 March 2018 Introduction Survivin, the unique member of the inhibitor of apoptosis (IAP) family, plays a major role both in the cell division process and in the inhibition of apoptosis (Mita et al., 2008). Survivin serves its regulatory function in cell division through its role in the chromosomal passenger complex (CPC), which regulates microtubule dynamics, stability, and mitotic progression (Giodini et al., 2002), and serves its antiapoptotic function through interaction with multiple proteins such as hepatitis B X-interacting protein, X-linked inhibitor of apoptosis (XIAP), and second mitochondrial-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low Pi (Smac/ DIABLO), which inhibits caspase activation (Peery et al., 2017). Survivin overexpression has been detected in a wide variety of malignancies, which results in cell-cycle checkpoints bypasses and promotion of aberrant pro- gression of transformed cells, unlike its minimal expres- sion in normal healthy tissues (Ryan et al., 2009). Survivin overexpression is correlated with adverse consequences including tumor aggressiveness, cancer relapse, therapy resistances (such as radiation therapy and chemotherapy), and poor clinical outcome (Li et al., 1998). Therefore, anticancer strategies have currently focused on survivin status both as a cancer biomarker and as a potential target for designing new approaches for cancer treatment. In this review, we introduce recently investigated survivin-targeted approaches besides different drugs and compounds that induced apoptosis in cancer cell lines through survivin downregulation. It is noteworthy, however, that survivin structure and physiological function are briefly reviewed. Survivin structure The IAPs is one of the well-known apoptosis inhibitor families consisting of several proteins such as NIAP, XIAP, Cellular inhibitor of apoptosis protein-1, cellular inhibitor of apoptosis protein-2, ILP2, livin, baculovirus inhibitor repeat (BIR)-repeat-containing ubiquitin-conjugating enzyme, and survivin (Jaiswal et al., 2015). All family members are char- acterized by a common motif in their structure called the BIR domain with a length of 70–80 amino acid (LaCasse et al., 1998). Survivin is the smallest member of this family, encoded by the baculoviral IAP repeat-containing 5 gene, consisting of four main exons and localized in the telomeric region of chromosome 17 (McKenzie and Grossman, 2012). Along with its major transcript (baculoviral IAP repeat- containing 5, survivin), which codes the wild-type protein 142 amino acids in length, alternative splicing generates four more splice variants coding survivin 2a, 2B, 3B, and ΔEx3, which serve different cell functions (Li, 2005). Survivin contains one single BIR domain in the N-terminal region and one coiled–coil motif in the C-terminal region. The BIR domain is critical for antiapoptotic function, whereas the coiled–coil motif is considered to interact with microtubules that are involved in cell division process (Wheatley and McNeish, 2005). X-ray crystallography showed that survivin structure forms a bow tie-shaped dimer. Review article 1 0959-8278 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/CEJ.0000000000000453 Copyright r 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.