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Journal of Cellular Biochemistry

Sorafenib induces endometrial carcinoma apoptosis by inhibiting Elk-1-dependent Mcl-1 transcription and inducing Akt/GSK3β-dependent protein degradation

Authors

  • Nian-Kang Sun,

    1. Department of Biochemistry and Molecular Biology, Chang Gung University College of Medicine, Taoyuan 333, Taiwan, Republic of China
    2. Division of Biomedical Sciences, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan, Republic of China
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  • Shang-Lang Huang,

    1. Department of Biochemistry and Molecular Biology, Chang Gung University College of Medicine, Taoyuan 333, Taiwan, Republic of China
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  • Ting-Chang Chang,

    1. Department of Medicine, Chang Gung University College of Medicine, Taoyuan 333, Taiwan, Republic of China
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  • Chuck C.-K. Chao

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Chang Gung University College of Medicine, Taoyuan 333, Taiwan, Republic of China
    2. Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan 333, Taiwan, Republic of China
    • Department of Biochemistry and Molecular Biology, Chang Gung University College of Medicine, Gueishan; Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Gueishan, Taoyuan 333, Taiwan, Republic of China.
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  • The authors declare no conflict of interest.

  • Author Contributions: C.C.-K.C. and N.-K.S. designed research; N.-K.S. and S.-L.H. performed research; C.C.-K.C., N.-K.S., and T.-C.C. analyzed data; and C.C.-K.C. wrote the paper.

Abstract

Endometrial carcinoma (EC) is one of the main gynecologic malignancies affecting women, but effective treatments are currently lacking. In the present study, we investigated the effect of sorafenib, a general kinase inhibitor, on several EC cell lines (HEC1A, HEC1B, and RL95-2). Sorafenib induced cell death in EC cells with the following order of sensitivity: HEC1A > HEC1B > RL95-2. Sorafenib suppressed several anti-apoptotic proteins in HEC1A cells, including myeloid cell leukemia 1 (Mcl-1). Ectopic overexpression of Mcl-1 prevented the cell killing effect of sorafenib. Sorafenib suppressed Mcl-1 at the gene transactivation level by inactivating the ERK/Elk-1 pathway. Accordingly, the inhibitory effect of sorafenib on Mcl-1 expression decreased following knockdown of Elk-1 using short-hairpin RNA (shRNA). Elk-1 overexpression rescued both the inhibitory effect of sorafenib on Mcl-1 expression and the cell killing effect of sorafenib. Furthermore, sorafenib reduced the stability of the Mcl-1 protein by enhancing its ubiquitination and degradation by the proteasome via the AKT/GSK3β and the ERK pathways. Similar results were detected in other EC cell lines. These results indicate that sorafenib induces apoptosis in EC cells by down-regulating the anti-apoptotic protein Mcl-1 via transcriptional inhibition and protein degradation. Our results thus support the notion that sorafenib may be used in endometrial cancer therapy. J. Cell. Biochem. 114: 1819–1831, 2013. © 2013 Wiley Periodicals, Inc.

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