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The Suppression of Aurora-A/STK15/BTAK Expression Enhances Chemosensitivity to Docetaxel in Human Esophageal Squamous Cell Carcinoma

Authors' Affiliations: ¹ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan and ² Department of Molecular Cytogenetics, Graduate School of Biomedical Science, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

Requests for reprints: Yutaka Shimada, Department of Surgery, Graduate School of Medicine, Kyoto University, Kawaracho 54, Shogoin Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3626; Fax: 81-75-751-4390; E-mail: shimada{at}kuhp.kyoto-u.ac.jp.

Purpose: We previously reported that the expression of Aurora-A was frequently up-regulated in human esophageal squamous cell carcinoma (ESCC) tissues as well as cell lines and the up-regulation contributed to a poor prognosis. In this study, we assessed the possibility of Aurora-A suppression as a therapeutic target for ESCC using ESCC cell lines.

Experimental Design: We established subclones using vector-based short hairpin RNA (shRNA). Then, we investigated the effect of Aurora-A suppression on proliferation and cell cycle changes in vitro. Next, chemosensitivity against docetaxel was investigated by tetrazolium salt–based proliferation assay (WST assay) and cell number determinations, and furthermore, the type of cell death induced by docetaxel was analyzed by flow cytometry. Finally, to examine the effect of Aurora-A shRNA on proliferation and chemosensitivity against docetaxel in vivo, a s.c. tumor formation assay in nude mice was done.

Results: We established two genetically different stable cell lines (510 A and 1440 A) in which levels of Aurora-A were reduced. Cell growth was inhibited by 38.7% in 510 A and by 24.3% in 1440 A in vitro compared with empty vector–transfected controls (510 m and 1440 m), and this growth inhibition was mediated through G₂-M arrest as confirmed by flow cytometry. Next, in a WST assay, the IC₅₀ for Aurora-A shRNA-transfected cells was lower than that of empty vector–transfected cells (510 A, 2.7 x 10^–7 mol/L; 510 m, 4.8 x 10^–7 mol/L; 1440 A, 2.6 x 10^–7 mol/L; 1440 m, 4.9 x 10^–7 mol/L). In addition, 0.3 nmol/L docetaxel induced a notable level of apoptosis in Aurora-A shRNA-transfected cells compared with empty vector–transfected cells. In the assay of s.c. tumors in nude mice, tumor growth in 510 A was inhibited by 36.1% compared with that in 510 m, and in tumors treated with docetaxel, the suppression of Aurora-A resulted in 44.0% tumor growth suppression in vivo.

Conclusions: These results indicated that Aurora-A might play an important role in chemosensitivity to docetaxel, and the suppression of its expression might be a potential therapeutic target for ESCC.

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