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

Chao Yuan Huang, Wei Tien Tai, Szu-Yuan Wu, Chih Ting Shih, Min Hsuan Chen, Ming Hsien Tsai, Chiung Wen Kuo, Chung Wai Shiau, Man Hsin Hung, Kuen Feng Chen

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Abstract

PURPOSE: 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.

Original languageEnglish
Pages (from-to)761-71
Number of pages11
JournalInternational Journal of Radiation Oncology Biology Physics
Volume95
Issue number2
DOIs
Publication statusPublished - Jun 1 2016

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phosphatases
src Homology Domains
Phosphoric Monoester Hydrolases
Hepatocellular Carcinoma
cancer
radiation therapy
Radiotherapy
therapy
homology
apoptosis
SH2 Domain-Containing Protein Tyrosine Phosphatases
cells
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Investigational Drugs
Apoptosis
Therapeutics
Radiation Tolerance
radiation tolerance
Recombinant Proteins
cultured cells

Keywords

  • Journal Article

Cite this

Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling. / Huang, Chao Yuan; Tai, Wei Tien; Wu, Szu-Yuan; Shih, Chih Ting; Chen, Min Hsuan; Tsai, Ming Hsien; Kuo, Chiung Wen; Shiau, Chung Wai; Hung, Man Hsin; Chen, Kuen Feng.

In: International Journal of Radiation Oncology Biology Physics, Vol. 95, No. 2, 01.06.2016, p. 761-71.

Research output: Contribution to journalArticle

Huang, Chao Yuan ; Tai, Wei Tien ; Wu, Szu-Yuan ; Shih, Chih Ting ; Chen, Min Hsuan ; Tsai, Ming Hsien ; Kuo, Chiung Wen ; Shiau, Chung Wai ; Hung, Man Hsin ; Chen, Kuen Feng. / Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling. In: International Journal of Radiation Oncology Biology Physics. 2016 ; Vol. 95, No. 2. pp. 761-71.
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title = "Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling",
abstract = "PURPOSE: 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.",
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author = "Huang, {Chao Yuan} and Tai, {Wei Tien} and Szu-Yuan Wu and Shih, {Chih Ting} and Chen, {Min Hsuan} and Tsai, {Ming Hsien} and Kuo, {Chiung Wen} and Shiau, {Chung Wai} and Hung, {Man Hsin} and Chen, {Kuen Feng}",
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TY - JOUR

T1 - Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling

AU - Huang, Chao Yuan

AU - Tai, Wei Tien

AU - Wu, Szu-Yuan

AU - Shih, Chih Ting

AU - Chen, Min Hsuan

AU - Tsai, Ming Hsien

AU - Kuo, Chiung Wen

AU - Shiau, Chung Wai

AU - Hung, Man Hsin

AU - Chen, Kuen Feng

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - PURPOSE: 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.

AB - PURPOSE: 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.

KW - Journal Article

U2 - 10.1016/j.ijrobp.2016.01.016

DO - 10.1016/j.ijrobp.2016.01.016

M3 - Article

C2 - 26960749

VL - 95

SP - 761

EP - 771

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

SN - 0360-3016

IS - 2

ER -