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

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.

[1]  Torben F. Ørntoft,et al.  Emmprin and Survivin Predict Response and Survival following Cisplatin-Containing Chemotherapy in Patients with Advanced Bladder Cancer , 2007, Clinical Cancer Research.

[2]  J C Reed,et al.  IAP family proteins--suppressors of apoptosis. , 1999, Genes & development.

[3]  D. Altieri,et al.  A p34(cdc2) survival checkpoint in cancer. , 2002, Cancer cell.

[4]  C. Schamberger,et al.  Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras , 2003, Oncogene.

[5]  John Calvin Reed.  Dysregulation of apoptosis in cancer. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  D. Metzler,et al.  Dynamic intracellular survivin in oral squamous cell carcinoma: underlying molecular mechanism and potential as an early prognostic marker , 2007, The Journal of pathology.

[7]  G. Rassidakis,et al.  Survivin expression predicts poorer prognosis in anaplastic large-cell lymphoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  P. Black,et al.  Quantitatively determined survivin expression levels are of prognostic value in human gliomas. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Jiandong Chen,et al.  Transcriptional Repression of the Anti-apoptoticsurvivin Gene by Wild Type p53* , 2002, The Journal of Biological Chemistry.

[10]  D. Altieri.  The case for survivin as a regulator of microtubule dynamics and cell-death decisions. , 2006, Current opinion in cell biology.

[11]  Fengzhi Li,et al.  Silencing of antiapoptotic survivin gene by multiple approaches of RNA interference technology. , 2004, BioTechniques.

[12]  G. Feldman,et al.  Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. , 2003, Blood.

[13]  A. MacKenzie,et al.  The inhibitors of apoptosis (IAPs) and their emerging role in cancer , 1998, Oncogene.

[14]  R. Medema,et al.  The case for Survivin as mitotic regulator. , 2006, Current opinion in cell biology.

[15]  D. Altieri,et al.  Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. , 1998, Cancer research.

[16]  Robert L. Margolis,et al.  Crystal Structure of Human Survivin Reveals a Bow Tie?Shaped Dimer with Two Unusual ?-Helical Extensions , 2000 .

[17]  W. R. Bishop,et al.  Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway , 2002, Oncogene.

[18]  F. Yamasaki,et al.  Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker , 2007, Journal of Neuro-Oncology.

[19]  H. Moriwaki,et al.  Expression of survivin and of antigen detected by a novel monoclonal antibody, T332, is associated with outcome of diffuse large B‐cell lymphoma and its subtypes , 2005, Pathology international.

[20]  J Diebold,et al.  Prognostic significance of survivin expression in diffuse large B-cell lymphomas. , 2000, Blood.

[21]  Nerea Martínez,et al.  Expression of the NF‐κB targets BCL2 and BIRC5/Survivin characterizes small B‐cell and aggressive B‐cell lymphomas, respectively , 2005, The Journal of pathology.

[22]  Jian Kuang,et al.  Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosphorylation. , 2002, Molecular biology of the cell.

[23]  B. Boman,et al.  Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. , 2001, Cancer research.

[24]  D. Altieri.  Survivin, versatile modulation of cell division and apoptosis in cancer , 2003, Oncogene.

[25]  William C Earnshaw,et al.  Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. , 2004, The Journal of cell biology.

[26]  D. Altieri,et al.  Transcriptional analysis of human survivin gene expression. , 1999, The Biochemical journal.

[27]  S. Cory,et al.  Life-or-death decisions by the Bcl-2 protein family. , 2001, Trends in biochemical sciences.

[28]  Jongdae Lee,et al.  IAP Suppression of Apoptosis Involves Distinct Mechanisms: the TAK1/JNK1 Signaling Cascade and Caspase Inhibition , 2002, Molecular and Cellular Biology.

[29]  K. Tanaka,et al.  Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  W. Earnshaw,et al.  INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis , 2001, Current Biology.

[31]  W. Sessa,et al.  Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. , 2001, The American journal of pathology.

[32]  M. Andersen,et al.  Survivin--a universal tumor antigen. , 2002, Histology and histopathology.

[33]  W. Woods,et al.  DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells , 2002, Journal of Pharmacology and Experimental Therapeutics.

[34]  A. Masamune,et al.  Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand and Its Receptor Expression and the Pathway of Apoptosis in Human Pancreatic Cancer , 2001, Pancreas.

[35]  G. Hudes,et al.  Phase II monotherapy study of YM155, a novel survivin suppressant, administered by 168-hour continuous infusion in previously treated hormone refractory prostate cancer (HRPC) , 2007 .

[36]  J C Reed,et al.  The Survivin saga goes in vivo. , 2001, The Journal of clinical investigation.

[37]  E. Felip,et al.  A novel anti-apoptosis gene: Re-expression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  A. Sato,et al.  Synergistic effect of survivin-specific small interfering RNA and topotecan in renal cancer cells: topotecan enhances liposome-mediated transfection by increasing cellular uptake. , 2007, International journal of oncology.

[39]  N. Nemoto,et al.  Survivin as a Prognostic Factor for Osteosarcoma Patients , 2006, Acta histochemica et cytochemica.

[40]  V. Vaira,et al.  Regulation of survivin expression by IGF-1/mTOR signaling , 2007, Oncogene.

[41]  M. Hatano,et al.  Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Seamus J. Martin,et al.  Inhibition of TNF-induced apoptosis by NF-κB , 1998 .

[43]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[44]  M. Kitagawa,et al.  IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy‐induced overexpression of multidrug resistance genes , 2006, American journal of hematology.

[45]  S. Korsmeyer,et al.  BCL-2 family members and the mitochondria in apoptosis. , 1999, Genes & development.

[46]  D. Altieri.  Coupling Apoptosis Resistance to the Cellular Sress Response: The IAP-Hsp90 Connection in Cancer , 2004, Cell cycle.

[47]  J. Downward,et al.  The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner. , 2000, Journal of cell science.

[48]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[49]  Alessandra Giodini,et al.  Regulation of microtubule stability and mitotic progression by survivin. , 2002, Cancer research.

[50]  Ryoma Ohi,et al.  The Chromosomal Passenger Complex Is Required for Chromatin-Induced Microtubule Stabilization and Spindle Assembly , 2004, Cell.

[51]  K. Shroyer,et al.  Expression of survivin in normal, hyperplastic, and neoplastic colonic mucosa. , 2001, Human pathology.

[52]  D. Altieri.  Human diploid fibroblasts are refractory to oncogene-mediated transformation. , 2004 .

[53]  Mahasti Saghatchian,et al.  Molecular targets and cancer therapeutics. , 2004, Drug discovery today.

[54]  John Calvin Reed,et al.  HBXIP functions as a cofactor of survivin in apoptosis suppression , 2003, The EMBO journal.

[55]  D. Altieri,et al.  Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. , 2004, The Journal of clinical investigation.

[56]  W. Sessa,et al.  Regulation of survivin function by Hsp90 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[57]  K. Uematsu,et al.  Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells , 2004, Oncogene.

[58]  J. McNiff,et al.  Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. , 1999, The Journal of investigative dermatology.

[59]  A. Schimmer.  Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice , 2004, Cancer Research.

[60]  M. Ohira,et al.  High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma , 2000, Oncogene.

[61]  D. Altieri,et al.  Anti-apoptosis gene, survivin, and prognosis of neuroblastoma , 1998, The Lancet.

[62]  H. Taubert,et al.  Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53 , 2004, Cancer Gene Therapy.

[63]  W. Gerald,et al.  Inactivation of the apoptosis effector Apaf-1 in malignant melanoma , 2001, Nature.

[64]  S. Fukuda,et al.  Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis. , 2001, Blood.

[65]  G. Salvesen,et al.  Apoptosis: IAP proteins: blocking the road to death's door , 2002, Nature Reviews Molecular Cell Biology.

[66]  C. Hager,et al.  Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation. , 2007, Cancer research.

[67]  John Calvin Reed,et al.  Endogenous Inhibitors of Caspases , 1999, Journal of Clinical Immunology.

[68]  R. Kerbel,et al.  Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. , 1999, Biochemical and biophysical research communications.

[69]  John Calvin Reed,et al.  An IAP-IAP Complex Inhibits Apoptosis* , 2004, Journal of Biological Chemistry.

[70]  R. Weiss,et al.  Urine detection of survivin and diagnosis of bladder cancer. , 2001, JAMA.

[71]  G. Yancopoulos,et al.  Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. , 2002, Microvascular research.

[72]  D. Altieri,et al.  A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma , 1997, Nature Medicine.

[73]  Fengzhi Li,et al.  Control of apoptosis and mitotic spindle checkpoint by survivin , 1998, Nature.

[74]  N. Sardesai,et al.  Detection of Newly Diagnosed Bladder Cancer, Bladder Cancer Recurrence and Bladder Cancer in Patients with Hematuria Using Quantitative RT-PCR of Urinary Survivin , 2007, Tumor Biology.

[75]  Y. Lotan,et al.  Survivin expression is associated with bladder cancer presence, stage, progression, and mortality. , 2006, Cancer.

[76]  V. Cryns,et al.  Proteases to die for. , 1998, Genes & development.

[77]  M. Fukuoka,et al.  Phase I study of YM155, a first-in-class survivin suppressant, in patients with advanced solid tumors in Japan , 2007 .

[78]  G. Sirugo,et al.  Induction of Apoptosis and Inhibition of Cell Proliferation bysurvivin Gene Targeting* , 1998, The Journal of Biological Chemistry.

[79]  R. Walker,et al.  Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients , 2007, British Journal of Cancer.

[80]  M. Daidone,et al.  Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. , 2002, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[81]  J. Pablos.  Inactivation of the apoptosis effector Apaf-1 in malignant melanoma , 2001 .

[82]  C. Qian,et al.  Suppression of colorectal tumor growth by regulated survivin targeting , 2006, Journal of Molecular Medicine.

[83]  L. Giacomelli,et al.  Expression of the apoptosis inhibitor protein Survivin in primary laryngeal carcinoma and cervical lymph node metastasis. , 2006, Anticancer research.

[84]  H. Sakamoto,et al.  DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of c-erbB-2 and survivin genes. , 2001, Cancer letters.

[85]  D. Altieri,et al.  The cancer antiapoptosis mouse survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression. , 1999, Cancer research.