Tumor Biology

, Volume 35, Issue 4, pp 2831–2836 | Cite as

Aurora-A: a potential DNA repair modulator

  • Yan Wang
  • Huizhen Sun
  • Ziliang Wang
  • Mingming Liu
  • Zihao Qi
  • Jiao Meng
  • Jianmin Sun
  • Gong Yang


It is well-known that overexpression of Aurora-A promotes tumorigenesis, but the role of Aurora-A in the development of cancer has not been fully investigated. Recent studies indicate that Aurora-A may confer cancer cell chemo- and radioresistance through dysregulation of cell cycle progression and DNA damage response. Direct evidences from literatures suggest that Aurora-A inhibits pRb, p53, p21waf1/cip1, and p27cip/kip but enhances Plk1, CDC25, CDK1, and cyclin B1 to repeal cell cycle checkpoints and to promote cell cycle progression. Other studies indicate that Aurora-A suppresses BRCA1, BRCA2, RAD51, poly(ADP ribose) polymerase (PARP), and gamma-H2AX to dysregulate DNA damage response. Aurora-A may also interact with RAS and Myc to control DNA repair indirectly. In this review, we summarized the potential role of Aurora-A in DNA repair from the current literatures and concluded that Aurora-A may function as a DNA repair modulator to control cancer cell radio- and chemosensitivity, and that Aurora-A-associated DNA repair molecules may be considered for targeted cancer therapy.


Aurora-A p53 BRCA1/2 DNA damage repair Radio- and Chemoresistance 


Conflicts of interest



  1. 1.
    Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998;20:189–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17:3052–65.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Li CC, Chu HY, Yang CW, Chou CK, Tsai TF. Aurora-A overexpression in mouse liver causes p53-dependent premitotic arrest during liver regeneration. Molecular cancer research : MCR. 2009;7:678–88.PubMedCrossRefGoogle Scholar
  4. 4.
    Meraldi P, Honda R, Nigg EA. Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev. 2004;14:29–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Yang G, Chang B, Yang F, Guo X, Cai KQ, Xiao XS, et al. Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2. Clin Cancer Res. 2010;16:3171–81.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Wang W, Zhang N, Wang J, Bu XM, Zhao CH. Inhibition of proliferation, viability, migration and invasion of gastric cancer cells by Aurora-A deletion. Asian Pac J Cancer Prev. 2011;12:2717–20.PubMedGoogle Scholar
  7. 7.
    Huck JJ, Zhang M, McDonald A, Bowman D, Hoar KM, Stringer B, et al. MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Molecular cancer research : MCR. 2010;8:373–84.PubMedCrossRefGoogle Scholar
  8. 8.
    Tomita M, Mori N. Aurora A selective inhibitor MLN8237 suppresses the growth and survival of HTLV-1-infected T-cells in vitro. Cancer Sci. 2010;101:1204–11.PubMedCrossRefGoogle Scholar
  9. 9.
    Jantscher F, Pirker C, Mayer CE, Berger W, Sutterluety H. Overexpression of Aurora-A in primary cells interferes with S-phase entry by diminishing Cyclin D1 dependent activities. Mol Cancer. 2011;10:28.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Zhang D, Hirota T, Marumoto T, Shimizu M, Kunitoku N, Sasayama T, et al. Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models. Oncogene. 2004;23:8720–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Marumoto T, Hirota T, Morisaki T, Kunitoku N, Zhang D, Ichikawa Y, et al. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells. 2002;7:1173–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Krystyniak A, Garcia-Echeverria C, Prigent C, Ferrari S. Inhibition of Aurora A in response to DNA damage. Oncogene. 2006;25:338–48.PubMedGoogle Scholar
  13. 13.
    Cazales M, Schmitt E, Montembault E, Dozier C, Prigent C, Ducommun B. CDC25B phosphorylation by Aurora-A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle. 2005;4:1233–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Gorgun G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, et al. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010;115:5202–13.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008;455:119–23.PubMedCrossRefGoogle Scholar
  16. 16.
    Seki A, Coppinger JA, Jang CY, Yates JR, Fang G. Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science. 2008;320:1655–8.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Qin L, Tong T, Song Y, Xue L, Fan F, Zhan Q. Aurora-A interacts with Cyclin B1 and enhances its stability. Cancer Lett. 2009;275:77–85.PubMedCrossRefGoogle Scholar
  18. 18.
    Dutertre S, Cazales M, Quaranta M, Froment C, Trabut V, Dozier C, et al. Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2-M transition. J Cell Sci. 2004;117:2523–31.PubMedCrossRefGoogle Scholar
  19. 19.
    Hu W, Kavanagh JJ, Deaver M, Johnston DA, Freedman RS, Verschraegen CF, et al. Frequent overexpression of STK15/Aurora-A/BTAK and chromosomal instability in tumorigenic cell cultures derived from human ovarian cancer. Oncol Res. 2005;15:49–57.PubMedGoogle Scholar
  20. 20.
    Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 2004;36:55–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Liu Q, Kaneko S, Yang L, Feldman RI, Nicosia SV, Chen J, et al. Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem. 2004;279:52175–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Warnock LJ, Raines SA, Milner J. Aurora A mediates cross-talk between N- and C-terminal post-translational modifications of p53. Cancer Biol Ther. 2011;12(12):1059–68.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Nair JS, Ho AL, Schwartz GK. The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent. Cell Cycle. 2012;11:807–17.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Madan E, Gogna R, Pati U. p53 Ser15 phosphorylation disrupts the p53-RPA70 complex and induces RPA70-mediated DNA repair in hypoxia. Biochem J. 2012;443:811–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Katayama H, Wang J, Treekitkarnmongkol W, Kawai H, Sasai K, Zhang H, et al. Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73. Cancer cell. 2012;21:196–211.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Chen SS, Chang PC, Cheng YW, Tang FM, Lin YS. Suppression of the STK15 oncogenic activity requires a transactivation-independent p53 function. EMBO J. 2002;21:4491–9.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Tian WJ, Feng WL, Wang HB, Huang SF, Cao WX, Huang ZG. Inhibitory effect of wild-type p53 gene on excessive replication of centrosomes in leukemia cell line K562. Ai Zheng. 2009;28:122–6.PubMedGoogle Scholar
  28. 28.
    Nikulenkov F, Spinnler C, Li H, Tonelli C, Shi Y, Turunen M, et al. Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis. Cell Death Differ. 2012;19(12):1992–2002.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Shao S, Wang Y, Jin S, Song Y, Wang X, Fan W, et al. Gadd45a interacts with aurora-A and inhibits its kinase activity. J Biol Chem. 2006;281:28943–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Sanchez R, Pantoja-Uceda D, Prieto J, Diercks T, Marcaida MJ, Montoya G, et al. Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase. J Biol Chem. 2010;285:22196–201.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Mao JH, Wu D, Perez-Losada J, Jiang T, Li Q, Neve RM, et al. Crosstalk between Aurora-A and p53: frequent deletion or downregulation of Aurora-A in tumors from p53 null mice. Cancer Cell. 2007;11:161–73.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Tao Y, Zhang P, Frascogna V, Lecluse Y, Auperin A, Bourhis J, et al. Enhancement of radiation response by inhibition of Aurora-A kinase using siRNA or a selective Aurora kinase inhibitor PHA680632 in p53-deficient cancer cells. Br J Cancer. 2007;97:1664–72.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Zhang D, Shimizu T, Araki N, Hirota T, Yoshie M, Ogawa K, et al. Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice. Oncogene. 2008;27:4305–14.PubMedCrossRefGoogle Scholar
  34. 34.
    Ouchi M, Fujiuchi N, Sasai K, Katayama H, Minamishima YA, Ongusaha PP, et al. BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem. 2004;279:19643–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Yang F, Guo X, Yang G, Rosen DG, Liu J. AURKA and BRCA2 expression highly correlate with prognosis of endometrioid ovarian carcinoma. Mod Pathol. 2011;24:836–45.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Wang XX, Liu R, Jin SQ, Fan FY, Zhan QM. Overexpression of Aurora-A kinase promotes tumor cell proliferation and inhibits apoptosis in esophageal squamous cell carcinoma cell line. Cell Res. 2006;16:356–66.PubMedCrossRefGoogle Scholar
  37. 37.
    Sourisseau T, Maniotis D, McCarthy A, Tang C, Lord CJ, Ashworth A, et al. Aurora-A expressing tumour cells are deficient for homology-directed DNA double strand-break repair and sensitive to PARP inhibition. EMBO Mol Med. 2010;2:130–42.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Moretti L, Niermann K, Schleicher S, Giacalone NJ, Varki V, Kim KW, et al. MLN8054, a small molecule inhibitor of aurora kinase a, sensitizes androgen-resistant prostate cancer to radiation. Int J Radiat Oncol Biol Phys. 2011;80:1189–97.PubMedCrossRefGoogle Scholar
  39. 39.
    Shin HJ, Kim JY, Hampson L, Pyo H, Baek HJ, Roberts SA, et al. Human papillomavirus 16 E6 increases the radiosensitivity of p53-mutated cervical cancer cells, associated with up-regulation of aurora A. Int J Radiat Biol. 2010;86:769–79.PubMedCrossRefGoogle Scholar
  40. 40.
    Tu Z, Aird KM, Bitler BG, Nicodemus JP, Beeharry N, Xia B, et al. Oncogenic RAS regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence. Dev Cell. 2011;21:1077–91.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Toulany M, Schickfluss TA, Eicheler W, Kehlbach R, Schittek B, Rodemann HP. Impact of oncogenic K-RAS on YB-1 phosphorylation induced by ionizing radiation. Breast Cancer Res. 2011;13:R28.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Tatsuka M, Sato S, Kitajima S, Suto S, Kawai H, Miyauchi M, et al. Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene. 2005;24:1122–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Tseng YS, Lee JC, Huang CY, Liu HS. Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway. BMC Cancer. 2009;9:435.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Yang G, Mercado-Uribe I, Multani AS, Sen S, ShihIe M, Wong KK, et al. RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora-A and BRCA2 in midbody during cytokinesis. International Journal of Cancer Journal International du Cancer. 2013;133:275–85.PubMedCrossRefGoogle Scholar
  45. 45.
    Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 2005;6:635–45.PubMedCrossRefGoogle Scholar
  46. 46.
    Guerra L, Albihn A, Tronnersjo S, Yan Q, Guidi R, Stenerlow B, et al. Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage. PLoS One. 2010;5:e8924.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Menssen A, Hermeking H. Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci U S A. 2002;99:6274–9.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Li Z, Van Calcar S, Qu C, Cavenee WK, Zhang MQ, Ren B. A global transcriptional regulatory role for c-Myc in Burkitt’s lymphoma cells. Proc Natl Acad Sci U S A. 2003;100:8164–9.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Song L, Dai T, Xie Y, Wang C, Lin C, Wu Z, et al. Up-regulation of miR-1245 by c-myc targets BRCA2 and impairs DNA repair. J Mol Cell Biol. 2012;4:108–17.PubMedCrossRefGoogle Scholar
  50. 50.
    Yang S, He S, Zhou X, Liu M, Zhu H, Wang Y, et al. Suppression of Aurora‐A oncogenic potential by c‐Myc downregulation. Exp Mol Med. 2010;42:759–67.Google Scholar
  51. 51.
    Otto T, Horn S, Brockmann M, Eilers U, Schuttrumpf L, Popov N, et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell. 2009;15:67–78.PubMedCrossRefGoogle Scholar
  52. 52.
    Brockmann M, Poon E, Berry T, Carstensen A, Deubzer HE, Rycak L, et al. Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell. 2013;24:75–89.PubMedCrossRefGoogle Scholar
  53. 53.
    Sehdev V, Peng D, Soutto M, Washington MK, Revetta F, Ecsedy J, et al. The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells. Mol Cancer Ther. 2012;11:763–74.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Lassmann S, Shen Y, Jutting U, Wiehle P, Walch A, Gitsch G, et al. Predictive value of Aurora-A/STK15 expression for late stage epithelial ovarian cancer patients treated by adjuvant chemotherapy. Clin Cancer Res. 2007;13:4083–91.PubMedCrossRefGoogle Scholar
  55. 55.
    Cammareri P, Scopelliti A, Todaro M, Eterno V, Francescangeli F, Moyer MP, et al. Aurora-A is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. Cancer Res. 2010;70:4655–65.PubMedCrossRefGoogle Scholar
  56. 56.
    Yang H, He L, Kruk P, Nicosia SV, Cheng JQ. Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells. Int J Cancer. 2006;119:2304–12.PubMedCrossRefGoogle Scholar
  57. 57.
    Guan Z, Wang XR, Zhu XF, Huang XF, Xu J, Wang LH, et al. Aurora-A, a negative prognostic marker, increases migration and decreases radiosensitivity in cancer cells. Cancer Res. 2007;67:10436–44.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Yan Wang
    • 1
    • 2
  • Huizhen Sun
    • 1
    • 2
  • Ziliang Wang
    • 1
    • 2
  • Mingming Liu
    • 1
    • 2
  • Zihao Qi
    • 1
    • 2
  • Jiao Meng
    • 1
    • 2
  • Jianmin Sun
    • 1
    • 2
  • Gong Yang
    • 1
    • 2
  1. 1.Cancer InstituteFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Department of Oncology, Shanghai MedicalFudan UniversityShanghaiChina

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