Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling

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• 作者：Chao-Yuan Huang ; MD ; PhD^&lowast ; ; ^&dagger ; ; Wei-Tien Tai ; PhD^&Dagger ; ; ^§ ; ; Szu-Yuan Wu ; MD^‖ ; ^¶ ; ; ^# ; ^&lowast ; &lowast ; ; Chih-Ting Shih ; MS^&Dagger ; ; Min-Hsuan Chen ; MS^&Dagger ; ; Ming-Hsien Tsai^&Dagger ; ; Chiung-Wen Kuo ; PhD^&dagger ; &dagger ; ; Chung-Wai Shiau ; PhD^&Dagger ; &Dagger ; ; Man-Hsin Hung ; MD^§ ; § ; ; ^‖‖ ; ^¶ ; ¶ ; ; ^## ; ^{cindybeaty@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Kuen-Feng Chen ; MD ; PhD^&Dagger ; ; ^§ ; ; ^{kfchen1970@ntu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：95
• 期：2
• 页码：761-771
• 全文大小：2064 K

文摘

Hepatocellular carcinoma (HCC) is among the most lethal human malignancies, and curative therapy is not an option for most patients. There is growing interest in the potential benefit of combining targeted therapies with radiation therapy (RT). This study aimed to characterize the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT.

Methods and Materials

HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T, and Huh-7) were treated with dovitinib, RT, or both, and apoptosis and signal transduction were analyzed.

Results

Dovitinib treatment resulted in Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1, diminished the effects of dovitinib on HCC cells. By ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Conversely, ectopic expression of SHP-1 or activation of SHP-1 by dovitinib enhanced the effects of RT against HCC in vitro and in vivo.

Conclusions

SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. Combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects.