Aurora-A, a Negative Prognostic Marker, Increases Migration and Decreases Radiosensitivity in Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2007-11, Vol.67 (21), p.10436-10444
• Main Authors: ZHONG GUAN, WANG, Xian-Ren, WENLIN HUANG, ZENG, Yi-Xin, CHEN, Fu-Jin, QUENTIN LIU, ZHU, Xiao-Feng, HUANG, Xue-Fei, JIE XU, WANG, Li-Hui, WAN, Xiang-Bo, LONG, Zi-Jie, LIU, Jian-Nan, FENG, Gong-Kan
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Aurora Kinases; Biological and medical sciences; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - radiotherapy; Cell Line, Tumor; Cell Movement; Humans; Laryngeal Neoplasms - mortality; Laryngeal Neoplasms - pathology; Laryngeal Neoplasms - radiotherapy; Medical sciences; Pharmacology. Drug treatments; Piperazines - pharmacology; Prognosis; Protein Serine-Threonine Kinases - analysis; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology; Radiation Tolerance; RNA, Small Interfering - pharmacology; Survival Rate; Tumor Suppressor Protein p53 - physiology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-1379

Centrosomal Aurora-A (Aur-A) kinase ensures proper spindle assembly and accurate chromosome segregation in mitosis. Overexpression of Aur-A leads to centrosome amplification, aberrant spindle, and consequent genetic instability. In the present study, Aur-A was found to be overexpressed in laryngeal squamous cell carcinoma (LSCC). Moreover, Aur-A expression was adversely correlated with median survival, and further identified as a potential independent factor for disease prognosis. Suppression of Aurora kinase activity chemically or genetically led to LSCC Hep2 cell cycle arrest and apoptotic cell death. Importantly, we found that Aur-A increases cell migration and this novel function was correlated with Akt1 activation. The enhanced cell migration induced by Aur-A overexpression could be abrogated by either small-molecule Akt1 inhibitor or short interfering RNA. VX-680, a selective Aurora kinase inhibitor, decreased Akt1 phosphorylation at Ser(473) and inhibited cell migration, but failed to do so in constitutive active Akt1 (myr-Akt1)-overexpressed cells. Moreover, our data suggested that overexpression of Aur-A kinase might also contribute to radioresistance of LSCC. Inhibiting Aur-A by VX-680 induced expression of p53 and potently sensitized cells to radiotherapy, leading to significant cell death. Ectopic overexpression of Aur-A, however, reduced p53 level and rendered cells more resistant to irradiation. Taken together, we showed that Aur-A kinase, a negative prognostic marker, promotes migration and reduces radiosensitivity in laryngeal cancer cells.