Survivin Splice Variants Are Not Essential for Mitotic Progression or Inhibition of Apoptosis Induced by Doxorubicin and Radiation

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2012 Mar 1

PMID 22375097

Citations 10

Authors

Naduparambil K Jacob

James V Cooley

Katsuyuki Shirai

Arnab Chakravarti

Affiliations

Soon will be listed here.

Abstract

Survivin is a critical regulator of mitosis, and an inhibitor of apoptosis which is overexpressed in almost all cancers. In the current study, cell cycle profiles of normal proliferating human umbilical vein endothelial cells, prostate cancer, and lung cancer cell lines expressing varying levels of survivin and its splice variants were compared using a novel functional complementation assay. Defects in chromosome segregation and cytokinesis that were observed after depletion of endogenous survivin were not complemented by any of the survivin splice variants: survivin-2B, survivin-3B, survivin-ΔEx3, or survivin-2A when expressed exogenously at a level comparable to endogenous full-length survivin. Survivin variants were not detectable at the endogenous protein level. Cancer cells with higher levels of full-length survivin and survivin-2B expression, exhibited reduced caspase-3 activation following doxorubicin treatment and radiation. Whereas earlier studies focused on function and expression levels of survivin specific to cancer cells, the current study brings forward the essential role of survivin in normal dividing cells. Full-length survivin was found to be associated with Aurora-B kinase in the chromosomal passenger complex and depletion of survivin mimics mitotic phenotypes observed after Aurora-B kinase inhibition, in cancer as well as normal proliferating cells. Thus, our study establishes survivin as a marker of proliferation, rather than a cancer specific marker. Therefore, systemic therapeutic interventions targeting survivin will affect cancer as well as normal proliferating cells.

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Survivin delta Ex3 overexpression in thyroid malignancies.

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References

Tamm I, Wang Y, Sausville E, Scudiero D, Vigna N, Oltersdorf T . IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 1998; 58(23):5315-20. View

Mahotka C, Wenzel M, Springer E, Gabbert H, Gerharz C . Survivin-deltaEx3 and survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res. 2000; 59(24):6097-102. View

Speliotes E, Uren A, Vaux D, Horvitz H . The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Mol Cell. 2000; 6(2):211-23. DOI: 10.1016/s1097-2765(00)00023-x. View

Zhu N, Gu L, Findley H, Li F, Zhou M . An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy. Oncogene. 2004; 23(45):7545-51. DOI: 10.1038/sj.onc.1208038. View

Li F, Ambrosini G, Chu E, Plescia J, Tognin S, Marchisio P . Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998; 396(6711):580-4. DOI: 10.1038/25141. View

Krieg A, Mahotka C, Krieg T, Grabsch H, Muller W, Takeno S . Expression of different survivin variants in gastric carcinomas: first clues to a role of survivin-2B in tumour progression. Br J Cancer. 2002; 86(5):737-43. PMC: 2375298. DOI: 10.1038/sj.bjc.6600153. View

Ruchaud S, Carmena M, Earnshaw W . Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol. 2007; 8(10):798-812. DOI: 10.1038/nrm2257. View

Boidot R, Vegran F, Lizard-Nacol S . Predictive value of survivin alternative transcript expression in locally advanced breast cancer patients treated with neoadjuvant chemotherapy. Int J Mol Med. 2009; 23(2):285-91. View

Span P, Tjan-Heijnen V, Heuvel J, de Kok J, Foekens J, Sweep F . Do the survivin (BIRC5) splice variants modulate or add to the prognostic value of total survivin in breast cancer?. Clin Chem. 2006; 52(9):1693-700. DOI: 10.1373/clinchem.2006.071613. View

10.

Asanuma K, Kobayashi D, Furuya D, Tsuji N, Yagihashi A, Watanabe N . A role for survivin in radioresistance of pancreatic cancer cells. Jpn J Cancer Res. 2002; 93(9):1057-62. PMC: 5927133. DOI: 10.1111/j.1349-7006.2002.tb02483.x. View

11.

Yamada Y, Kuroiwa T, Nakagawa T, Kajimoto Y, Dohi T, Azuma H . Transcriptional expression of survivin and its splice variants in brain tumors in humans. J Neurosurg. 2003; 99(4):738-45. DOI: 10.3171/jns.2003.99.4.0738. View

12.

Ling X, Yang J, Tan D, Ramnath N, Younis T, Bundy B . Differential expression of survivin-2B and survivin-DeltaEx3 is inversely associated with disease relapse and patient survival in non-small-cell lung cancer (NSCLC). Lung Cancer. 2005; 49(3):353-61. PMC: 2827179. DOI: 10.1016/j.lungcan.2005.03.037. View

13.

Knauer S, Bier C, Schlag P, Fritzmann J, Dietmaier W, Rodel F . The survivin isoform survivin-3B is cytoprotective and can function as a chromosomal passenger complex protein. Cell Cycle. 2007; 6(12):1502-9. View

14.

Atlasi Y, Mowla S, Ziaee S . Differential expression of survivin and its splice variants, survivin-DeltaEx3 and survivin-2B, in bladder cancer. Cancer Detect Prev. 2009; 32(4):308-13. DOI: 10.1016/j.cdp.2008.12.001. View

15.

Caldas H, Jiang Y, Holloway M, Fangusaro J, Mahotka C, Conway E . Survivin splice variants regulate the balance between proliferation and cell death. Oncogene. 2005; 24(12):1994-2007. DOI: 10.1038/sj.onc.1208350. View

16.

Carmena M, Earnshaw W . The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 2003; 4(11):842-54. DOI: 10.1038/nrm1245. View

17.

Fangusaro J, Jiang Y, Holloway M, Caldas H, Singh V, Boue D . Survivin, Survivin-2B, and Survivin-deItaEx3 expression in medulloblastoma: biologic markers of tumour morphology and clinical outcome. Br J Cancer. 2005; 92(2):359-65. PMC: 2361849. DOI: 10.1038/sj.bjc.6602317. View

18.

Nouraee N, Mowla S, Ozhand A, Parvin M, Ziaee S, Hatefi N . Expression of survivin and its spliced variants in bladder tumors as a potential prognostic marker. Urol J. 2009; 6(2):101-8. View

19.

de Maria S, Pannone G, Bufo P, Santoro A, Serpico R, Metafora S . Survivin gene-expression and splicing isoforms in oral squamous cell carcinoma. J Cancer Res Clin Oncol. 2008; 135(1):107-16. DOI: 10.1007/s00432-008-0433-z. View

20.

Conway E, Pollefeyt S, Cornelissen J, DeBaere I, Ong K, Baens M . Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions. Blood. 2000; 95(4):1435-42. View