AURORA KİNAZLARIN KANSER VE HÜCRESEL SÜREÇLERDEKİ ROLÜ

Öz

Aurora kinazlar, Aurora A, B ve C şeklinde tanımlanan üç üyeye sahip, hücre döngüsünün düzenlenmesinde kritik rolleri olan yüksek oranda korunmuş serin/treonin kinaz ailesine ait proteinlerdir. Aurora kinazlar, kromozom stabilitesinin korunmasında önemli rolleri olan mitotik düzenleyiciler olarak hizmet etmektedir. Mitozdaki çeşitli olaylarda kritik roller üstlenen Aurora kinazlar, kromozomal ve sitoskeletal olayların koordinasyonu, iğ ipliği oluşumu kontrolü ve sitokinez gibi olaylarda görev alarak hücre döngüsünün sorunsuz ilerlemesini sağlamaktadır. Mitotik fonksiyonlarının yanı sıra, Aurora kinazlar mayoz bölünmenin düzenlenmesi süreçlerinde de yer almaktadırlar. Aurora kinazların gen amplifikasyonu/mutasyonu ve aşırı ifadesi çeşitli solid ve hematolojik kanserlerde tespit edilmiştir. Aurora kinazlar mitotik rolleri ile ilişkilendirilen onkojenik fonksiyonları ile kanser hücrelerinin çoğalması ve hayatta kalmalarını sağlamaktadırlar. Aurora kinaz aktivitesinin bozulması, sentrozom fonksiyonunda, iğ ipliklerinin oluşumunda, kromozomal hizalanmada ve sitokinezde sorunlara neden olarak mitotik anormallikler ve genetik istikrarsızlığa yol açmaktadır. Bu bulgular, Aurora kinazların kanserdeki önemli fonksiyonlarını vurgulayarak kanser terapötikleri için değerli hedefler olarak tanınmalarını sağlamaktadır. Bu derleme, Aurora kinazların yapı ve fonksiyonlarına genel bir bakış sunarak, bu kinazların kanserdeki onkojenik rollerini aydınlatmaktadır.

Anahtar Kelimeler

• Aurora kinazlar
• serin/treonin kinazlar
• kanser
• hücre döngüsü düzenleyicileri
• onkogenler

Aurora Kinases: Their Role in Cancer and Cellular Processes

Abstract

Aurora kinases, belonging to a highly conserved family of serine/threonine kinases with critical roles in the regulation of the cell cycle, comprise three members: Aurora kinase A, B, and C, which serve as key mitotic regulators essential for maintaining chromosome stability. Aurora kinases play crucial roles in multiple events in mitotic such as the coordination of chromosomal and cytoskeletal events, regulation of the spindle assembly checkpoint pathway and cytokinesis to ensure the smooth progression of the cell cycle. Besides their mitotic functions, Aurora kinases are also involved in the regulation of meiosis. Gene amplification/mutation and overexpression of Aurora kinases have been detected in various solid and haematological cancers. In human tumours, Aurora kinases exhibit oncogenic roles associated with their mitotic roles, which drive the cancer cell proliferation and survival. Deregulation of Aurora kinase activity causes failure in centrosome function, spindle assembly, chromosomal alignment, and cytokinesis, eventually resulting in the mitotic abnormalities and genetic instability. These findings emphasize the crucial functions of Aurora kinases in cancer, prompting their recognition as valuable targets for cancer therapy. This review provides an overview of the structures and functions of Aurora kinases and sheds light on their oncogenic roles in cancer.

Keywords

• Aurora kinases
• serine/threonine kinases
• cancer
• cell cycle regulators
• oncogenes

Kaynakça

1. Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003;4:842–54. https://doi.org/10.1038/nrm1245.
2. Moreira-Nunes CA, Mesquita FP, Portilho AJ de S, Mello Júnior FAR, Maués JH da S, Pantoja L da C, et al. Targeting aurora kinases as a potential prognostic and therapeutical biomarkers in pediatric acute lymphoblastic leukaemia. Sci Rep 2020;10:21272. https://doi.org/10.1038/s41598-020-78024-8.
3. Mou PK, Yang EJ, Shi C, Ren G, Tao S, Shim JS. Aurora kinase A, a synthetic lethal target for precision cancer medicine. Exp Mol Med 2021;53:835–47. https://doi.org/10.1038/s12276-021-00635-6.
4. Glover DM, Leibowitz MH, McLean DA, Parry H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 1995;81:95–105. https://doi.org/10.1016/0092-8674(95)90374-7.
5. Schumacher JM, Golden A, Donovan PJ. AIR-2: An Aurora/Ipl1-related Protein Kinase Associated with Chromosomes and Midbody Microtubules Is Required for Polar Body Extrusion and Cytokinesis in Caenorhabditis elegans Embryos. The Journal of Cell Biology 1998;143:1635. https://doi.org/10.1083/jcb.143.6.1635.
6. Schumacher JM, Ashcroft N, Donovan PJ, Golden A. A highly conserved centrosomal kinase, AIR-1, is required for accurate cell cycle progression and segregation of developmental factors in Caenorhabditis elegans embryos. Development 1998;125:4391–402. https://doi.org/10.1242/dev.125.22.4391.
7. Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN, Rogister B. The functional diversity of Aurora kinases: a comprehensive review. Cell Div 2018;13:7. https://doi.org/10.1186/s13008-018-0040-6.
8. Brown JR, Koretke KK, Birkeland ML, Sanseau P, Patrick DR. Evolutionary relationships of Aurora kinases: Implications for model organism studies and the development of anti-cancer drugs. BMC Evolutionary Biology 2004;4:39. https://doi.org/10.1186/1471-2148-4-39.

9. Bernard M, Sanseau P, Henry C, Couturier A, Prigent C. Cloning of STK13, a third human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on chromosome 19q13.3-ter. Genomics 1998;53:406–9. https://doi.org/10.1006/geno.1998.5522.
10. Quartuccio SM, Schindler K. Functions of Aurora kinase C in meiosis and cancer. Front Cell Dev Biol 2015;3:50. https://doi.org/10.3389/fcell.2015.00050.
11. Borah NA, Reddy MM. Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer. Molecules 2021;26:1981. https://doi.org/10.3390/molecules26071981.
12. Pandya PN, Mankad AU, Raval RM. Role of Aurora Kinases in Cancer: A Comprehensive Review. RJLBPCS 2018;04.
13. Garrido G, Vernos I. Non-centrosomal TPX2-Dependent Regulation of the Aurora A Kinase: Functional Implications for Healthy and Pathological Cell Division. Front Oncol 2016;6:88. https://doi.org/10.3389/fonc.2016.00088.
14. Tang A, Gao K, Chu L, Zhang R, Yang J, Zheng J. Aurora kinases: novel therapy targets in cancers. Oncotarget 2017;8:23937–54. https://doi.org/10.18632/oncotarget.14893.
15. Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL, Golemis EA. Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci 2013;70:661–87. https://doi.org/10.1007/s00018-012-1073-7.
16. Janeček M, Rossmann M, Sharma P, Emery A, Huggins DJ, Stockwell SR, et al. Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2. Sci Rep 2016;6:28528. https://doi.org/10.1038/srep28528.
17. Sun G, Rong D, Li Z, Sun G, Wu F, Li X, et al. Role of Small Molecule Targeted Compounds in Cancer: Progress, Opportunities, and Challenges. Front Cell Dev Biol 2021;9:694363. https://doi.org/10.3389/fcell.2021.694363.
18. Polverino F, Naso FD, Asteriti IA, Palmerini V, Singh D, Valente D, et al. The Aurora-A/TPX2 Axis Directs Spindle Orientation in Adherent Human Cells by Regulating NuMA and Microtubule Stability. Curr Biol 2021;31:658-667.e5. https://doi.org/10.1016/j.cub.2020.10.096.
19. Berdnik D, Knoblich JA. Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis - PubMed 2002. https://pubmed.ncbi.nlm.nih.gov/11967150/ (accessed April 4, 2024).
20. Kaestner P, Stolz A, Bastians H. Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells. Mol Cancer Ther 2009;8:2046–56. https://doi.org/10.1158/1535-7163.MCT-09-0323.
21. Li M, Liu H, Zhao Q, Han S, Zhou L, Liu W, et al. Targeting Aurora B kinase with Tanshinone IIA suppresses tumor growth and overcomes radioresistance. Cell Death Dis 2021;12:152. https://doi.org/10.1038/s41419-021-03434-z.
22. Borah NA, Sradhanjali S, Barik MR, Jha A, Tripathy D, Kaliki S, et al. Aurora Kinase B Expression, Its Regulation and Therapeutic Targeting in Human Retinoblastoma. Invest Ophthalmol Vis Sci 2021;62:16. https://doi.org/10.1167/iovs.62.3.16.
23. Bavetsias V, Linardopoulos S. Aurora Kinase Inhibitors: Current Status and Outlook. Front Oncol 2015;5:278. https://doi.org/10.3389/fonc.2015.00278.
24. Titova E, Shagieva G, Dugina V, Kopnin P. The Role of Aurora B Kinase in Normal and Cancer Cells. Biochemistry (Mosc) 2023;88:2054–62. https://doi.org/10.1134/S0006297923120088.
25. Marima R, Hull R, Penny C, Dlamini Z. Mitotic syndicates Aurora Kinase B (AURKB) and mitotic arrest deficient 2 like 2 (MAD2L2) in cohorts of DNA damage response (DDR) and tumorigenesis. Mutat Res Rev Mutat Res 2021;787:108376. https://doi.org/10.1016/j.mrrev.2021.108376.
26. Nguyen AL, Schindler K. Specialize and Divide (Twice): Functions of Three Aurora Kinase Homologs in Mammalian Oocyte Meiotic Maturation. Trends Genet 2017;33:349–63. https://doi.org/10.1016/j.tig.2017.03.005.
27. Yan X, Wu Y, Li Q, Cao L, Liu X, Saiyin H, et al. Cloning and characterization of a novel human Aurora C splicing variant. Biochem Biophys Res Commun 2005;328:353–61. https://doi.org/10.1016/j.bbrc.2004.12.168.
28. Katayama H, Sasai K, Kawai H, Yuan Z-M, 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. https://doi.org/10.1038/ng1279.
29. Bejar JF, DiSanza Z, Quartuccio SM. The oncogenic role of meiosis-specific Aurora kinase C in mitotic cells. Experimental Cell Research 2021;407:112803. https://doi.org/10.1016/j.yexcr.2021.112803.
30. Abdul Azeez KR, Chatterjee S, Yu C, Golub TR, Sobott F, Elkins JM. Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP. Nat Commun 2019;10:3166. https://doi.org/10.1038/s41467-019-11085-0.
31. Kimmins S, Crosio C, Kotaja N, Hirayama J, Monaco L, Höög C, et al. Differential functions of the Aurora-B and Aurora-C kinases in mammalian spermatogenesis. Mol Endocrinol 2007;21:726–39. https://doi.org/10.1210/me.2006-0332.
32. Dieterich K, Soto Rifo R, Faure AK, Hennebicq S, Ben Amar B, Zahi M, et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet 2007;39:661–5. https://doi.org/10.1038/ng2027.
33. Ounis L, Zoghmar A, Coutton C, Rouabah L, Hachemi M, Martinez D, et al. Mutations of the aurora kinase C gene causing macrozoospermia are the most frequent genetic cause of male infertility in Algerian men. Asian J Androl 2015;17:68–73. https://doi.org/10.4103/1008-682X.136441.
34. Schindler K, Davydenko O, Fram B, Lampson MA, Schultz RM. Maternally recruited Aurora C kinase is more stable than Aurora B to support mouse oocyte maturation and early development. Proceedings of the National Academy of Sciences 2012;109:E2215–22. https://doi.org/10.1073/pnas.1120517109.
35. Gavriilidis P, Giakoustidis A, Giakoustidis D. Aurora Kinases and Potential Medical Applications of Aurora Kinase Inhibitors: A Review. J Clin Med Res 2015;7:742–51. https://doi.org/10.14740/jocmr2295w.
36. Sansregret L, Swanton C. The Role of Aneuploidy in Cancer Evolution. Cold Spring Harb Perspect Med 2017;7:a028373. https://doi.org/10.1101/cshperspect.a028373.
37. Gupta D, Kumar M, Saifi S, Rawat S, Ethayathulla AS, Kaur P. A comprehensive review on role of Aurora kinase inhibitors (AKIs) in cancer therapeutics. Int J Biol Macromol 2024;265:130913. https://doi.org/10.1016/j.ijbiomac.2024.130913.
38. Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN, Gandara DR. Aurora kinases as anticancer drug targets. Clin Cancer Res 2008;14:1639–48. https://doi.org/10.1158/1078-0432.CCR-07-2179.
39. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017;45:W98–102. https://doi.org/10.1093/nar/gkx247.
40. Du R, Huang C, Liu K, Li X, Dong Z. Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy. Mol Cancer 2021;20:15. https://doi.org/10.1186/s12943-020-01305-3.
41. 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. https://doi.org/10.1074/jbc.M406802200.
42. Fu J, Bian M, Jiang Q, Zhang C. Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 2007;5:1–10. https://doi.org/10.1158/1541-7786.MCR-06-0208.
43. D’Assoro AB, Haddad T, Galanis E. Aurora-A Kinase as a Promising Therapeutic Target in Cancer. Front Oncol 2016;5:295. https://doi.org/10.3389/fonc.2015.00295.
44. Naso FD, Boi D, Ascanelli C, Pamfil G, Lindon C, Paiardini A, et al. Nuclear localisation of Aurora-A: its regulation and significance for Aurora-A functions in cancer. Oncogene 2021;40:3917–28. https://doi.org/10.1038/s41388-021-01766-w.
45. Lin X, Xiang X, Hao L, Wang T, Lai Y, Abudoureyimu M, et al. The role of Aurora-A in human cancers and future therapeutics. Am J Cancer Res 2020;10:2705–29.
46. Tavernier N, Thomas Y, Vigneron S, Maisonneuve P, Orlicky S, Mader P, et al. Bora phosphorylation substitutes in trans for T-loop phosphorylation in Aurora A to promote mitotic entry. Nat Commun 2021;12:1899. https://doi.org/10.1038/s41467-021-21922-w.
47. Taga M, Hirooka E, Ouchi T. Essential Roles of mTOR/Akt Pathway in Aurora-A Cell Transformation. Int J Biol Sci 2009;5:444–50.
48. Dar AA, Goff LW, Majid S, Berlin J, El-Rifai W. Aurora Kinases’ Inhibitors – Rising Stars in Cancer Therapeutics? Mol Cancer Ther 2010;9:268. https://doi.org/10.1158/1535-7163.MCT-09-0765.
49. den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A, et al. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 2010;116:1498–505. https://doi.org/10.1182/blood-2009-11-251074.
50. Jiang J, Wang J, Yue M, Cai X, Wang T, Wu C, et al. Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis. Cancer Cell 2020;37:200-215.e5. https://doi.org/10.1016/j.ccell.2020.01.001.
51. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–42. https://doi.org/10.1056/NEJM200104053441402.
52. Greuber EK, Smith-Pearson P, Wang J, Pendergast AM. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer 2013;13:559–71. https://doi.org/10.1038/nrc3563.
53. Yang J, Ikezoe T, Nishioka C, Udaka K, Yokoyama A. Bcr-Abl activates AURKA and AURKB in chronic myeloid leukemia cells via AKT signaling. Int J Cancer 2014;134:1183–94. https://doi.org/10.1002/ijc.28434.
54. Marsola APZC, Simões BP, Palma LC, Berzoti-Coelho MG, Burin SM, de Castro FA. Expression of Hippo signaling pathway and Aurora kinase genes in chronic myeloid leukemia. Med Oncol 2018;35:26. https://doi.org/10.1007/s12032-018-1079-6.
55. González-Loyola A, Fernández-Miranda G, Trakala M, Partida D, Samejima K, Ogawa H, et al. Aurora B Overexpression Causes Aneuploidy and p21Cip1 Repression during Tumor Development. Mol Cell Biol 2015;35:3566–78. https://doi.org/10.1128/MCB.01286-14.
56. Pohl A, Azuma M, Zhang W, Yang D, Ning Y, Winder T, et al. Pharmacogenetic profiling of Aurora kinase B is associated with overall survival in metastatic colorectal cancer. Pharmacogenomics J 2011;11:93–9. https://doi.org/10.1038/tpj.2010.18.
57. Huang D, Huang Y, Huang Z, Weng J, Zhang S, Gu W. Relation of AURKB over-expression to low survival rate in BCRA and reversine-modulated aurora B kinase in breast cancer cell lines. Cancer Cell Int 2019;19:166. https://doi.org/10.1186/s12935-019-0885-z.
58. Vischioni B, Oudejans JJ, Vos W, Rodriguez JA, Giaccone G. Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell lung carcinoma patients. Mol Cancer Ther 2006;5:2905–13. https://doi.org/10.1158/1535-7163.MCT-06-0301.
59. Chieffi P. Aurora B: A new promising therapeutic target in cancer. Intractable Rare Dis Res 2018;7:141–4. https://doi.org/10.5582/irdr.2018.01018.
60. Nie M, Wang Y, Yu Z, Li X, Deng Y, Wang Y, et al. AURKB promotes gastric cancer progression via activation of CCND1 expression. Aging (Albany NY) 2020;12:1304–21. https://doi.org/10.18632/aging.102684.
61. Qi G, Ogawa I, Kudo Y, Miyauchi M, Siriwardena BSMS, Shimamoto F, et al. Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch 2007;450:297–302. https://doi.org/10.1007/s00428-006-0360-9.
62. Zeng WF, Navaratne K, Prayson RA, Weil RJ. Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 2007;60:218–21. https://doi.org/10.1136/jcp.2006.036806.
63. Yasen M, Mizushima H, Mogushi K, Obulhasim G, Miyaguchi K, Inoue K, et al. Expression of Aurora B and alternative variant forms in hepatocellular carcinoma and adjacent tissue. Cancer Science 2009;100:472–80. https://doi.org/10.1111/j.1349-7006.2008.01068.x.
64. Tatsuka M, Katayama H, Ota T, Tanaka T, Odashima S, Suzuki F, et al. Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res 1998;58:4811–6.
65. Chieffi P, Cozzolino L, Kisslinger A, Libertini S, Staibano S, Mansueto G, et al. Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. The Prostate 2006;66:326–33. https://doi.org/10.1002/pros.20345.
66. Sinisi AA, Chieffi P, Pasquali D, Kisslinger A, Staibano S, Bellastella A, et al. EPN: a novel epithelial cell line derived from human prostate tissue. In Vitro Cell Dev Biol Anim 2002;38:165–72. https://doi.org/10.1290/1071-2690(2002)038<0165:EANECL>2.0.CO;2.
67. Staibano S, Franco R, Mezza E, Chieffi P, Sinisi A, Pasquali D, et al. Loss of oestrogen receptor beta, high PCNA and p53 expression and aneuploidy as markers of worse prognosis in ovarian granulosa cell tumours. Histopathology 2003;43:254–62. https://doi.org/10.1046/j.1365-2559.2003.01706.x.
68. Sorrentino R, Libertini S, Pallante PL, Troncone G, Palombini L, Bavetsias V, et al. Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 2005;90:928–35. https://doi.org/10.1210/jc.2004-1518.
69. Libertini S, Abagnale A, Passaro C, Botta G, Barbato S, Chieffi P, et al. AZD1152 negatively affects the growth of anaplastic thyroid carcinoma cells and enhances the effects of oncolytic virus dl922-947. Endocrine-Related Cancer 2010;18:129–41. https://doi.org/10.1677/ERC-10-0234.
70. Nguyen TT, Silva FN, Golemis EA. Aurora Kinases as Therapeutic Targets in Head and Neck Cancer. Cancer J 2022;28:387–400. https://doi.org/10.1097/PPO.0000000000000614.
71. Stefani A, Piro G, Schietroma F, Strusi A, Vita E, Fiorani S, et al. Unweaving the mitotic spindle: A focus on Aurora kinase inhibitors in lung cancer. Front Oncol 2022;12:1026020. https://doi.org/10.3389/fonc.2022.1026020.
72. Khan J, Ezan F, Crémet J-Y, Fautrel A, Gilot D, Lambert M, et al. Overexpression of Active Aurora-C Kinase Results in Cell Transformation and Tumour Formation. PLoS One 2011;6:e26512. https://doi.org/10.1371/journal.pone.0026512.
73. Gabillard J-C, Ulisse S, Baldini E, Sorrenti S, Cremet J-Y, Coccaro C, et al. Aurora-C interacts with and phosphorylates the transforming acidic coiled-coil 1 protein. Biochem Biophys Res Commun 2011;408:647–53. https://doi.org/10.1016/j.bbrc.2011.04.078.
74. Spengler D. The protein kinase Aurora C phosphorylates TRF2. Cell Cycle 2007;6:2579–80. https://doi.org/10.4161/cc.6.20.4781.
75. Cully M, Shiu J, Piekorz RP, Muller WJ, Done SJ, Mak TW. Transforming acidic coiled coil 1 promotes transformation and mammary tumorigenesis. Cancer Res 2005;65:10363–70. https://doi.org/10.1158/0008-5472.CAN-05-1633.
76. Ghayad SE, Vendrell JA, Bieche I, Spyratos F, Dumontet C, Treilleux I, et al. Identification of TACC1, NOV, and PTTG1 as new candidate genes associated with endocrine therapy resistance in breast cancer. J Mol Endocrinol 2009;42:87–103. https://doi.org/10.1677/JME-08-0076.
77. Shammas MA. Telomeres, lifestyle, cancer, and aging. Curr Opin Clin Nutr Metab Care 2011;14:28–34. https://doi.org/10.1097/MCO.0b013e32834121b1.
78. Umene K, Banno K, Kisu I, Yanokura M, Nogami Y, Tsuji K, et al. Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors. Biomed Rep 2013;1:335–40. https://doi.org/10.3892/br.2013.91.
79. Cirak Y, Furuncuoglu Y, Yapicier O, Aksu A, Cubukcu E. Aurora A overexpression in breast cancer patients induces taxane resistance and results in worse prognosis. J BUON 2015;20:1414–9.
80. Hole S, Pedersen AM, Lykkesfeldt AE, Yde CW. Aurora kinase A and B as new treatment targets in aromatase inhibitor-resistant breast cancer cells. Breast Cancer Res Treat 2015;149:715–26. https://doi.org/10.1007/s10549-015-3284-8.
81. Sun J-M, Yang L-N, Xu H, Chang B, Wang H-Y, Yang G. Inhibition of Aurora A promotes chemosensitivity via inducing cell cycle arrest and apoptosis in cervical cancer cells. Am J Cancer Res 2015;5:1133–45.
82. Gabrielli B, Bokhari F, Ranall MV, Oo ZY, Stevenson AJ, Wang W, et al. Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer. Mol Cancer Ther 2015;14:2753–61. https://doi.org/10.1158/1535-7163.MCT-15-0506.
83. Casorzo L, Dell’Aglio C, Sarotto I, Risio M. Aurora kinase A gene copy number is associated with the malignant transformation of colorectal adenomas but not with the serrated neoplasia progression. Human Pathology 2015;46:411–8. https://doi.org/10.1016/j.humpath.2014.11.016.
84. Saiprasad G, Chitra P, Manikandan R, Sudhandiran G. Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated phosphoinositide-3-kinase/Akt/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis. Eur J Cancer 2014;50:2489–507. https://doi.org/10.1016/j.ejca.2014.06.013.
85. Jin S, Wang X, Tong T, Zhang D, Shi J, Chen J, et al. Aurora‐A enhances malignant development of esophageal squamous cell carcinoma (ESCC) by phosphorylating β‐catenin. Mol Oncol 2015;9:249–59. https://doi.org/10.1016/j.molonc.2014.08.002.
86. Wang X, Li X, Li C, He C, Ren B, Deng Q, et al. Aurora-A modulates MMP-2 expression via AKT/NF-κB pathway in esophageal squamous cell carcinoma cells. Acta Biochim Biophys Sin (Shanghai) 2016;48:520–7. https://doi.org/10.1093/abbs/gmw030.
87. Honma K, Nakanishi R, Nakanoko T, Ando K, Saeki H, Oki E, et al. Contribution of Aurora-A and -B expression to DNA aneuploidy in gastric cancers. Surg Today 2014;44:454–61. https://doi.org/10.1007/s00595-013-0581-x.
88. Katsha A, Belkhiri A, Goff L, El-Rifai W. Aurora kinase A in gastrointestinal cancers: time to target. Mol Cancer 2015;14:106. https://doi.org/10.1186/s12943-015-0375-4.
89. Premkumar DR, Jane EP, Pollack IF. Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells. Cancer Biol Ther 2015;16:233–43. https://doi.org/10.4161/15384047.2014.987548.
90. Reichardt W, Jung V, Brunner C, Klein A, Wemmert S, Romeike BFM, et al. The putative serine/threonine kinase gene STK15 on chromosome 20q13.2 is amplified in human gliomas. Oncology Reports 2003;10:1275–9. https://doi.org/10.3892/or.10.5.1275.
91. Kim S-J, Jang JE, Cheong J-W, Eom J-I, Jeung H-K, Kim Y, et al. Aurora A kinase expression is increased in leukemia stem cells, and a selective Aurora A kinase inhibitor enhances Ara-C-induced apoptosis in acute myeloid leukemia stem cells. Korean J Hematol 2012;47:178–85. https://doi.org/10.5045/kjh.2012.47.3.178.
92. Wei T-YW, Wu P-Y, Wu T-J, Hou H-A, Chou W-C, Teng C-LJ, et al. Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA. Cancer Res 2017;77:494–508. https://doi.org/10.1158/0008-5472.CAN-16-1004.
93. Lo Iacono M, Monica V, Saviozzi S, Ceppi P, Bracco E, Papotti M, et al. Aurora Kinase A expression is associated with lung cancer histological-subtypes and with tumor de-differentiation. J Transl Med 2011;9:100. https://doi.org/10.1186/1479-5876-9-100.
94. Gu J, Gong Y, Huang M, Lu C, Spitz MR, Wu X. Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians. Carcinogenesis 2007;28:350–5. https://doi.org/10.1093/carcin/bgl149.
95. 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. https://doi.org/10.1038/sj.onc.1208293.
96. Tanaka H, Nakashiro K, Iwamoto K, Tokuzen N, Fujita Y, Shirakawa R, et al. Targeting Aurora kinase A suppresses the growth of human oral squamous cell carcinoma cells in vitro and in vivo. Oral Oncol 2013;49:551–9. https://doi.org/10.1016/j.oraloncology.2013.02.002.
97. Do T-V, Xiao F, Bickel LE, Klein-Szanto AJ, Pathak HB, Hua X, et al. Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion. Oncogene 2014;33:539–49. https://doi.org/10.1038/onc.2012.632.
98. Davidson B, Nymoen DA, Elgaaen BV, Staff AC, Tropé CG, Kærn J, et al. BUB1 mRNA is significantly co-expressed with AURKA and AURKB mRNA in advanced-stage ovarian serous carcinoma. Virchows Arch 2014;464:701–7. https://doi.org/10.1007/s00428-014-1577-7.
99. Toughiri R, Li X, Du Q, Bieberich CJ. Phosphorylation of NuMA by Aurora-A kinase in PC-3 prostate cancer cells affects proliferation, survival, and interphase NuMA localization. J Cell Biochem 2013;114:823–30. https://doi.org/10.1002/jcb.24421.
100. Lee ECY, Frolov A, Li R, Ayala G, Greenberg NM. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 2006;66:4996–5002. https://doi.org/10.1158/0008-5472.CAN-05-2796.
101. Zhang Y, Jiang C, Li H, Lv F, Li X, Qian X, et al. Elevated Aurora B expression contributes to chemoresistance and poor prognosis in breast cancer. Int J Clin Exp Pathol 2015;8:751–7.
102. Twu N-F, Yuan C-C, Yen M-S, Lai C-R, Chao K-C, Wang P-H, et al. Expression of Aurora kinase A and B in normal and malignant cervical tissue: high Aurora A kinase expression in squamous cervical cancer. Eur J Obstet Gynecol Reprod Biol 2009;142:57–63. https://doi.org/10.1016/j.ejogrb.2008.09.012.
103. Tuncel H, Shimamoto F, Kaneko Guangying Qi H, Aoki E, Jikihara H, Nakai S, et al. Nuclear Aurora B and cytoplasmic Survivin expression is involved in lymph node metastasis of colorectal cancer. Oncol Lett 2012;3:1109–14. https://doi.org/10.3892/ol.2012.633.
104. Subramaniyan B, Kumar V, Mathan G. Effect of sodium salt of Butrin, a novel compound isolated from Butea monosperma flowers on suppressing the expression of SIRT1 and Aurora B kinase-mediated apoptosis in colorectal cancer cells. Biomed Pharmacother 2017;90:402–13. https://doi.org/10.1016/j.biopha.2017.03.086.
105. Diaz RJ, Golbourn B, Shekarforoush M, Smith CA, Rutka JT. Aurora kinase B/C inhibition impairs malignant glioma growth in vivo. J Neurooncol 2012;108:349–60. https://doi.org/10.1007/s11060-012-0835-2.
106. Hartsink-Segers SA, Zwaan CM, Exalto C, Luijendijk MWJ, Calvert VS, Petricoin EF, et al. Aurora kinases in childhood acute leukemia: the promise of aurora B as therapeutic target. Leukemia 2013;27:560–8. https://doi.org/10.1038/leu.2012.256.
107. Takeshita M, Koga T, Takayama K, Ijichi K, Yano T, Maehara Y, et al. Aurora-B overexpression is correlated with aneuploidy and poor prognosis in non-small cell lung cancer. Lung Cancer 2013;80:85–90. https://doi.org/10.1016/j.lungcan.2012.12.018.
108. Smith SL, Bowers NL, Betticher DC, Gautschi O, Ratschiller D, Hoban PR, et al. Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability. Br J Cancer 2005;93:719–29. https://doi.org/10.1038/sj.bjc.6602779.
109. Pannone G, Hindi S a. H, Santoro A, Sanguedolce F, Rubini C, Cincione RI, et al. Aurora B expression as a prognostic indicator and possible therapeutic target in oral squamous cell carcinoma. Int J Immunopathol Pharmacol 2011;24:79–88. https://doi.org/10.1177/039463201102400110.
110. Chen Y-J, Chen C-M, Twu N-F, Yen M-S, Lai C-R, Wu H-H, et al. Overexpression of Aurora B is associated with poor prognosis in epithelial ovarian cancer patients. Virchows Arch 2009;455:431–40. https://doi.org/10.1007/s00428-009-0838-3.
111. Fadri-Moskwik M, Weiderhold KN, Deeraksa A, Chuang C, Pan J, Lin S-H, et al. Aurora B is regulated by acetylation/deacetylation during mitosis in prostate cancer cells. FASEB J 2012;26:4057–67. https://doi.org/10.1096/fj.12-206656.
112. Zekri A, Lesan V, Ghaffari SH, Tabrizi MH, Modarressi MH. Gene amplification and overexpression of Aurora-C in breast and prostate cancer cell lines. Oncol Res 2012;20:241–50. https://doi.org/10.3727/096504013x13589503482978.
113. Fujii S, Srivastava V, Hegde A, Kondo Y, Shen L, Hoshino K, et al. Regulation of AURKC expression by CpG island methylation in human cancer cells. Tumor Biol 2015;36:8147–58. https://doi.org/10.1007/s13277-015-3553-5.
114. Tsou J-H, Chang K-C, Chang-Liao P-Y, Yang S-T, Lee C-T, Chen Y-P, et al. Aberrantly expressed AURKC enhances the transformation and tumourigenicity of epithelial cells. J Pathol 2011;225:243–54. https://doi.org/10.1002/path.2934.
115. Hosseini S, Hashemzadeh S, Estiar MA, Ebrahimzadeh R, Fakhree MBA, Yousefi B, et al. Expression Analysis of Aurora-C and Survivin, Two Testis-Specific Genes, in Patients with Colorectal Cancer. Clin Lab 2015;61:475–80. https://doi.org/10.7754/clin.lab.2014.141017.