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TGF-β1 mediates the radiation response of prostate cancer

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Abstract

Radiotherapy is the main treatment modality for prostate cancer. This study investigated the role of TGF-β1 in biological sequelae and tumor regrowth following irradiation, which are critical for the clinical radiation response of prostate cancer. Human and murine prostate cancer cell lines, and corresponding hormone-refractory (HR) cells, were used to examine the radiation response by clonogenic assays in vitro and tumor growth delay in vivo. Biological changes after irradiation, including cell death and tumor regrowth, were examined by experimental manipulation of TGF-β1 signaling. The correlations among tumor radiation responses, TGF-β1 levels, and regulatory T cells (Tregs) recruitment were also evaluated using animal experiments. HR prostate cancer cells appeared more radioresistant and had higher expression of TGF-β1 compared to hormone-sensitive (HS) cells. TGF-β1 expression was positively linked to irradiation and radioresistance, as demonstrated by in vitro and in vivo experiments. Inhibition of TGF-β1 increased tumor inhibition and DNA damage after irradiation. When mice were irradiated with a sub-lethal dose, the regrowth of irradiated tumors was significantly correlated with TGF-β1 levels and Tregs accumulation in vivo. Furthermore, blocking TGF-β1 clearly attenuated Tregs accumulation and tumor regrowth following treatment. These data demonstrate that TGF-β1 is important in determining the radiation response of prostate cancer, including tumor cell killing and the tumor microenvironment. Therefore, concurrent treatment with a TGF-β1 inhibitor is a potential therapeutic strategy for increasing the radiation response of prostate cancer, particularly for more aggressive or HR cancer cells.

Key message

• HR prostate cancer cells appeared more radioresistant and had higher expression of TGF-β1.

• TGF-β1 was positively linked to the radiation resistance of prostate cancer.

• Tumor regrowth following irradiation was significantly correlated with TGF-β1 and Tregs levels.

• Blocking TGF-β1 significantly attenuated RT-induced DNA repair and Tregs.

• TGF-β1 inhibitor increases the radiation response of HR cancer cells.

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Competing interests

The author(s) indicated no potential conflict of interest.

Funding sources

The study was supported by National Science Council, Taiwan. Grant 101-2314-B-182-062-MY3,

Disclosure

The authors declare no conflict of interests related to this study.

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Authors and Affiliations

  1. Department of Urology, Chang Gung Memorial Hospital, KeeLung, Taiwan

    Chun-Te Wu

  2. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chun-Te Wu, Ching-Chuan Hsieh, Tzu-Chen Yen, Wen-Cheng Chen & Miao-Fen Chen

  3. Department of General Surgery, Chang-Gung Memorial Hospital, Chiayi, Taiwan

    Ching-Chuan Hsieh

  4. Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Linko, Taiwan

    Tzu-Chen Yen

  5. Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Wen-Cheng Chen & Miao-Fen Chen

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  1. Chun-Te Wu
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  4. Wen-Cheng Chen
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  5. Miao-Fen Chen
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Correspondence to Miao-Fen Chen.

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Cite this article

Wu, CT., Hsieh, CC., Yen, TC. et al. TGF-β1 mediates the radiation response of prostate cancer. J Mol Med 93, 73–82 (2015). https://doi.org/10.1007/s00109-014-1206-6

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  • DOI: https://doi.org/10.1007/s00109-014-1206-6

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