Current Cancer Therapy Reviews, 2006, 2, 73-79 73

1573-3947/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.

Tumor Control by Manipulation of the Human Anti-Apoptotic SurvivinGene

Zakir Khan, Pratiksha Bhadouria, Radha Gupta and Prakash S. Bisen*,†

Department of Biotechnology, J.C. Bose Institute of Life Sciences, Bundelkhand University, Jhansi, U.P. India

Abstract: Survivin is a relatively unique member of the inhibitor of apoptosis protein (IAP) family. It contains a single

baculovirus IAP repeat (BIR) domain. It is involved in the control of cell cycle and inhibition of apoptosis. Survivin is of

interest because it is specifically up-regulated in cancer cells and completely down-regulated and undetectable in normal

adult tissues. Thus, survivin has proved to be a promising therapeutic target for normal anti-cancer therapy. Survivin

protects the fast dividing tumor cells against default apoptosis to facilitate aberrant mitosis. Down-regulation of survivin

with multiple approaches, suppress tumor progression and induce apoptosis on its own or in combination with

chemotherapy and radiotherapy.

Keywords: Survivin, IAPs, Apoptosis, Caspases, Ribozyme, p53.

INTRODUCTION

Survivin, a member of inhibitor of apoptosis protein(IAP) family, is characterized by a unique structure thatdiscriminates it from other members of the IAP family [1,2].It contains only a single BIR repeat and lacks a carboxyterminal Ring finger domain [3-5]. Survivin is a criticalregulator of multiple processes, including proliferation andapoptosis and its expression appears to be a consistentfeature of hyperproliferative lesions contributing to theformation of hyperplasia [6,7]. It is expressed in G2/M phaseof cell cycle to support rapidly dividing cell machinery [1,3]and helps in proper segregation of chromosomes during celldivision [6,7]. Survivin is abundantly expressed inembryonic tissues and in a wide range of cancer tissues butundetectable in normal differentiated tissues [3].Overexpression of survivin in cancer may overcome cellcycle checkpoints to facilitate aberrant progression oftransformed cells through mitosis [1,2]. To make an idealdrug target, an apoptosis regulator should be preferentiallyexpressed in tumor cells but not in normal tissues, andinterference with its expression/ function should be sufficientto facilitate cell death, either alone, or in combination withchemotherapeutic drugs or ultraviolet/ -irradiation. It hasbeen observed that the human survivin gene may fulfill bothof these prerequisites [8].

Several chemotherapeutic agents kill tumor cells throughapoptosis [8]. It has been found that survivin expression ishigh when tumor cells are treated with anticancer agents[8,9] by counteracting the effect of chemotherapeutic agentsand provides resistance to apoptosis [8,9]. Down regulationof survivin sensitize tumor cells to apoptosis induced bychemotherapy and radiotherapy in many types of cancer[10]. Exploitation of survivin signaling pathway may offernew therapeutic alternatives for cancer treatment.

*Address correspondence to this author at the J.C. Bose Institute of Life

Sciences, Bundelkhand University, Jhansi-284128, U.P., India; E-mail:

prakash_bisen@hotmail.com

†Present Address: Jaipur National University, Jaipur, India

Differential expression of survivin in cancer, comparedto most normal tissues, makes survivin a candidate for amolecular marker of cancer [1,3]. There is good evidencethat survivin may provide a quick prognostic indicator foridentifying patients at risk of recurrent disease [11]. Survivinand/or its auto-antibody present in biological fluids of cancerpatients could provide them a potential diagnostic tool [12].

STRUCTURE AND DISTRIBUTION OF SURVIVIN

Survivin is a 16.3 kD protein consisting of 142 aminoacids. The gene encoding survivin is of 14.5 kb, which islocated at the telomeric region of the chromosome 17 [11]. Ithas four exons and three introns (Fig. 1). Survivin is thesmallest member of the IAP family having two defineddomains including N-terminal Zn

+2 –binding domain linked

to 65 Ao amphipathic C-terminal alpha-helix [12,13]. It is

homodimeric, arranged through hydrophobic surface of theBIR domain of each survivin monomer [4,5]. Several splicevariants of survivin have been identified, such as survivin-delta Ex3 lacking exon 3 and survivin-2B retaining a part ofintron 2 as a cryptic exon (Fig. 1). A complex regulatorybalance exists amongst the isoforms of survivin that maydetermine the response to pro-apoptotic stimuli in tissues andseveral types of cancer [14]. Survivin-deltaEx3 has a uniquecarboxyl terminus sequence containing nuclear localizationsignal, which is found exclusively in the survivin-deltaEx3for an implicated sub-cellular targeting includingmitochondria and nucleus. Both survivin and survivin-deltaEx3 carry anti-apoptotic properties, whereas, survivin-2B is deficient in anti-apoptotic properties which may enablesurvivin-2B as a naturally occurring antagonist of anti-apoptotic survivin variants [15,16].

In mitosis, survivin has been shown to localize to variouscomponents of the mitotic apparatus, such as centrosomesand possibly microtubules. The location of survivin isabnormal in tumor cells as it is present throughout thecytoplasm [13,16].

FUNCTIONS OF SURVIVIN

There are two major types of pathway, extrinsic andintrinsic, that cause programmed cell death. An extrinsic

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74 Current Cancer Therapy Reviews, 2006, Vol. 2, No. 1 Bisen et al.

pathway is initiated by ligation of death receptors on the cellsurface (CD95/ Fas receptor, TNF-alpha) and acts throughthe activation of initiator caspase 8. An intrinsic pathway istriggered by multiple death signal either intracellular (un-repaired DNA damage) or environmental culminating toderegulation of the mitochondrial function. As a result, thepermeability of the outer mitochondrial membrane isincreased leading to release of proteins, cyt-c and Smac/DIABLO [2,15,16]. These proteins activate initiator caspase-9 that mediates apoptosome formation [2].

Molecular mechanism(s) of survivin action are not fullyelucidated and are at least in some aspects, controversial.Nevertheless, it is well accepted that survivin is an inhibitorof apoptosis and interferes with cell-cycle progression andmicrotubule stability. In general, mammalian IAPs, blockapoptosis by direct or indirect inhibition of initiator caspase-9 or terminal effector caspases 3 and 7 (Figs. 1 and 2).Studies suggested that survivin inhibits the intrinsic pathwayof apoptosis by interacting with post-mitochondrial events[17-19]. Several hypotheses exist to explain the mechanismsof anti-apoptotic activity of survivin. They might directlybind and inhibit caspases like any another IAPs, such as,XIAP [17]. Smac/DIABLO may act as a pro-apoptoticprotein through its participation in the activation of caspase-9 (Apoptosome formation). It may inhibit apoptosis throughantagonizing the pro-apoptotic ability due to its affinity withSmac/DIABLO [19] (Figs. 2 and 3).

In addition to anti-apoptotic function, survivin alsoregulates cell division because of its presence on the mitoticmachinery of dividing cells. Targeted survivin has resultedin aberrant mitotic progression, leading to failed cytokinesisand multinucleation [6,18,20-22]. Survivin is indispensableduring embryonic development. The homozygous deletion inmice leads to inevitable lethality at day 4-5 due to defects inmitotic spindles formation [13]. The apparent requirement ofsurvivin in normal cell division suggests that overexpressionof survivin in tumors could perturb normal cell cycle control.

FACTORS INDUCING SURVIVIN EXPRESSION

The expression of survivin is undetectable in normaldifferentiated cells but slowly expressed in fast dividing

normal cells, such as, CD34+ bone marrow derived stemcells, basal epithelial cells thymocytes and basal epithelialcells of normal uterine cervix [18,23,24]. Survivinexpression is very high in most cancers, particularly colon,lung, breast, brain and melanoma [12]. The molecularmechanisms of survivin overexpression in cancer seem to becomplex and are only partially understood. It is very likelythat multiple pathways are involved in the reactivation of thesurvivin gene.

Several molecular mechanisms in survivinoverexpression in tumor cells have been elucidated. In thenormal ovaries, survivin exon 1 is silenced by methylationbut it becomes demethylated and transcriptionally active inovarian cancer [12]. In neuroblastoma, amplification of17q25, comprising survivin locus has been reported [23,24].The transcriptional factor such as, p53 has been reported toregulate survivin-expression in various human cancer celllines [25,26]. In many cancers such as, gastric, pancreatic,prostate, lung, and epidermoid carcinomas, a correlationbetween p53 accumulation and survivin expression has beendemonstrated [27,28].

DOWN REGULATION OF SURVIVIN

Anti-Sense Technology

Anti-sense technology, with its potential to selectivelycontrol gene expression and cellular phenotype, is provinguseful as a therapeutic application. Several types of anti-sense approaches (viz. antisense oligonucleotides, antisenseRNA, and small interfering RNA) can be used to inhibitexpression of a target genes (Fig. 4).

Down regulation of survivin by a targeted anti-senseoligonucleotide appears to be an effective gene therapy tocombat several cancers (Fig. 4). Transfection of cancer cellwith antisense of survivin enhances sensitivity of tumor cellsto chemotherapy and radiotherapy. Several anti-survivinoligonucleotides have been tested for their ability to blocksurvivin expression in tumor cell lines. Anti senseoligonucleotide 4003 was found to be the most effective ingrowth inhibition and apoptosis in lung carcinoma cell lines[29].

Fig. (1). Survivin and its splice variants, Survivin–2B, Survivin EX 3. Pre-mRNA of survivin has four exons and an extra exon 2B (A).

Survivin-2B m-RNA has four exons and an extra exon-2B (B). Survivin mRNA has all four exons, but not exon-2B (C). Survivin EX 3

mRNA has three exons (exon 1, 2, 4) but not exon 3 and extra exon-2B (D).

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Most of the mesothelioma cancer cells underwentapoptosis and were more sensitive to chemotherapy andradiotherapy when treated with 20-mer phosphorothioateanti-sense oligonucleotide targeting nucleotides 232-251 ofsurvivin mRNA [30]. Growth of lymphoma cell lines wassignificantly inhibited by using anti-sense oligonucleotide(ASO) [31]. Treatment of colon cancer by adenoviral anti-sense vectors (pAd-CMV-SAS), resulted in an increase ofthe Go/G1 phase population in the cell cycle and increasedtheir sensitivity to chemotherapeutic drugs in vitro, [32]. In

PC-3 prostate cancer cell treatment with anti-sense survivincDNA caused nuclear fragmentation, hypodiploidy, cleavageof a 32- kDa proform caspase-3 to active caspase-3 andproteolysis of the caspase substrate poly (ADP) ribosepolymerase [33]. In another study, similar observation hasbeen seen with human neuroblastoma cell line SK-N-MC[34].

Expression of survivin gene can be checked byinterference RNA including both interfering RNA (siRNA)and short hairpin RNA (shRNA). These interfering RNA can

Fig. (2). Apoptotic Pathways and the site of surviving antiapoptotic action.

Intrinsic and extrinsic apoptotic pathways are shown that coverage into a common downstream pathway of effecter caspase activation. In

intrinsic pathway Cyt-c released from mitochondria in response to several stresses. Cyt-c interacts with Apaf-1 and procaspase-9 in presence

of dATP to form apoptosome complex that leads to activation of procaspase-9. Active caspase-9 activates effector caspases-3, 7, and 6,

which in turn induce apoptosis. Survivin most probably blocks, directly and/or indirectly, caspase 9 activation. It may directly inhibit initiator

caspase-9 and effector caspases-3, 7. Smac/DIABLO is a proapoptotic protein that inhibits activity of IAPs (XIAP). Survivin antagonize the

activity of Smac/DIABLO and may helps in the action of another IAPs (XIAP).

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be chemically synthesized and transfected into cells ordirectly expressed intracellularly from a plasmid DNA orfrom an adenoviral vector [35]. Transfection of cancer linesby adenoviral vector harboring a tandem-type Si-RNAexpression unit targeting survivin resulted in geneknockdown and induced apoptosis [36,37]. These cancercells, once infected with Adv-siSurv, displayed remarkablyattenuated growth potential, both in vitro and in vivo.Moreover, intratumoral injection of Adv-siSurv significantlysuppressed tumor growth in a genograft model using U251glioma cells. A short hairpin RNA (sh- RNA), containingtwo 20 to 21 bp reverse repeat motifs of survivin targetsequence with 4 to 8 bp spacer, effectively down regulateexpression survivin in liver cancer cell lines Hep G2andSMMC-7721, after transfection [38]. These findings suggestthat targeting of survivin using antisense technology mayhave a potential role in the selective therapy of cancer.

Dominant Negative Construct

In this technology an essential amino acid of the proteinis replaced by another amino acid, which leads to the loss offunction. But this nonfunctional protein has same target asnormal protein. Dominant negative mutant compete withnormal protein for their target and suppress the function ofnormal protein. Several dominant negative constructs havebeen discovered for survivin, from which T34A mutant ofsurvivin is best known [10]. Transduction of breast, cervical,prostate, lung and colorectal cancer cell lines with pAd-T34A (replication deficient adenovirus vector encoding a

nonphosphorylable The34Ala mutant survivin) increasedcyt-c release from mitochondria, processing of caspase-3 tothe active subunits of approximately 17 and 19 kDa,increased caspase-3 catalytic activity, and facilitated tumorcell apoptosis induced by taxol and adriamycin anticancerdrugs [39]. In malignant HeLa cells, trasfection with survivinmutant (survivin-N and survivin T34A) could partiallyreverse the malignancy of HeLa cells [40].

When dominant negative mutant of survivin, replacingthe cysteine residue at amino acid 84 with alanine(Cys84Ala) was introduced into BCG-823 and MKN-45gastric cell lines, the trasfectants exhibited abnormalmorphology, with decreased cell growth and increased rateof spontaneous apoptosis [41]. In PC-3 prostate cancer cellline, transfection with C84A mutant was sufficient tovisualize all biochemical hallmarks of apoptosis includinghypoploid DNA content, caspase 3 activities, and cleavageof caspase substrates [33].

Acetylation and Deacetylation Pathway

In eukaryotic cells, histone acetylation/deacetylation isimportant in transcriptional regulation [42]. Histone acetyltransferases (HATs) are recruited by transcription factors

and

are associated with activation of transcription, whereashistone deacetylases (HDACs) are involved in transcriptionalsilencing. The histone

acetylation is tightly controlled by the

dynamic equilibrium between competing HATs and HDACs

[42,43]. Histone acetyltransferases, as transcriptioncoactivators, catalyze the addition of acetyl groups on the e-

Fig. (3). Models of Survivin in the inhibition of apoptosis. Survivin can directly interact with caspases and inhibit them to suppress

apoptosis (A,B). XIAP is a strong inhibitor of apoptosis, which interacts directly with caspases and inhibits them. Smac/DIABLO is the

negative regulator of XIAP. Survivin may interact with Smac/DIABLO that ultimately leads to inhibition of apoptosis (C).

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Human Anti-Apoptotic Survivin Gene Current Cancer Therapy Reviews, 2006, Vol. 2, No. 1 77

amino group of lysine residues in the NH2-terminal tails ofcore histones. Conversely, HDACs as transcriptioncorepressors, remove the acetyl groups from the acetylatedlysines in histones [42,44,45]. Abnormality in these enzymescan disturb the expression of several apoptotic and cell cycleregulatory genes including survivin.

Inhibition of HDACs is emerging as a new strategy inhuman cancer therapy. Several drugs have been discovered,which specifically inhibit activity of HDAC. An importantdrug, clamydocin, used as a potent inhibitor of cellproliferation is a potent inhibitor of HDAC [46]. Like otherHDAC inhibitor, clamydocin induces the expression ofhyperacetylated histon H3 and H4 in cancer cells, increasethe expression of p21 (cip/waf1), and causes anaccumulation of cells in G2/M phase of the cell cycle. Inaddition, clamydicin induces apoptosis by activatingcaspase-3, which in turn leads to the cleavage of p21(cip/waf1) and drives cells from growth arrest into apoptosis.Clamydocin decreases the level of survivin, which ismediated by proteasome-mediated degradation. LAQ824,another inhibitor of HDAC, also down regulates the levels ofsurvivin and induces apoptosis of cancer cells [47].

RIBOZYME MEDIATED DEGRADATION OFSURVIVIN

Survivin expression can be inhibited by ribozyme.Survivin specific mRNA undergoes cleavage due toribozyme treatment resulting in inhibition of translation and

consequent retardation in tumor growth (Fig. 4). Twohammerhead ribozymes viz., RZ1 and RZ2, targeting humansurvivin mRNA have been designed [48]. Transduction ofMCF-7 cancer cell lines with adenovirus encoding theribozyme resulted in a significant reduction of survivinmRNA and protein as well and sensitized the cells toapoptosis. Infected PC-3 cells by adenoviral vector thatencodes a ribozyme targeting 3’ end of the survivin mRNAincreased susceptibility of PC-3 and DU145 cancer cells toapoptosis. These treatments increased susceptibility of PC-3and DU145 cancer cells to apoptosis [49]. In another study,transduction of melanoma cell lines JR8 and M14 withvector carrying ribozyme sequence lead to decrease ofsurvivin level and sensitized cancer cells to radiotherapy andchemotherapy [50,51].

Immunotherapy

Tumor cells express antigens that can be recognized bythe host immune system in the form of short peptidesbinding to major histocompatibility complex (MHC)molecules. It is recently discovered that immune responseagainst survivin derived epitopes can be induced [52].Several survivin derived epitopes have been tested to inducecytotoxic T lymphocyte activity against tumor cell. Dendriticcells were transduced successfully with an adenoviral vectorcontaining a full-length dominant negative survivin gene.Immunization with these dendritic cells induced T cellimmune response against three different survivin derivedHLA-A2 matching peptides. They found significant CTL

Fig. (4). Schematic representation of inhibition of survivin synthesis by ribozyme mediated degradation and anti-sense technology. In these

techniques essential nucleotide sequences which are common in splice variants of survivin were selected for the inhibition of expression.

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activity against HLA-A2-positive MCF-7 tumor cells thatexpress survivin [53].

Recently, an HLA-24-restricted immunogenic peptide-based vaccination (survivin-2B 80-88, AYACNTSTL) toneutralize survivin-2B splice variant, which is abnormallyexpressed in various types of tumor tissues and tumor celllines has been subjected to phase I trial on patients withadvanced or recurrent colorectal cancer [54]. Immunotherapyof cancer based on survivin may give promising hope.

CONCLUSION

Survivin belongs to an IAP family of proteins that playsan important role in cell cycle progression and cancer cellviability. It is one of the proteins that is specially expressedin most cancer cells. It may, therefore, be a good marker forcancer detection and may serve as an attractive therapeutictarget. Survivin is expressed in the majority of variouscancers studied. Various strategies to target survivin incancer cells are currently under investigation with promisingresults in vivo and in vitro models both. Moreover, somecurrently explored anti-cancer agents might mediate theiranti-cancer effects by inhibiting the survivin pathway.

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Received: July 22, 2005 Revised: October 14, 2005 Accepted: October 19, 2005

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