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Maspin mediates the gemcitabine sensitivity of hormone-independent prostate cancer

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Tumor Biology

Abstract

Androgen deprivation therapy has constituted the main treatment for prostate cancer; however, tumors ultimately progress to hormone-independent prostate cancer (HIPC), and suitable therapeutic strategies for HIPC are not available. Maspin, which is also known as mammary serine protease inhibitor, has been suggested to be a valuable focus for targeted cancer therapy. Specifically, maspin has been shown to be upregulated after androgen ablation therapy. Gemcitabine is used as a first-line therapy for metastatic castration-resistant prostate cancer, but its disease control rate is low. Furthermore, the role of maspin in the therapeutic efficacy of gemcitabine for HIPC remains unclear. The expression levels of maspin in PC-3 and DU145 cells were determined by real-time PCR and Western blotting. Furthermore, the expression of maspin was silenced using shRNA technology to generate maspin-KD cells. The cytotoxicity of gemcitabine to prostate cancer cells was assessed using 3-[4,5-dimethylthiazol-2-yl]-3,5-diphenyl tetrazolium bromide (MTT) assays, whereas flow cytometry analyses and annexin V-propidium iodide (PI) apoptosis assays were used to assess the ability of gemcitabine to induce apoptosis in maspin-KD and control cells. Additionally, the expression patterns of anti-apoptosis proteins (myeloid cell leukemia 1 (Mcl-1) and B cell lymphoma 2 (Bcl-2)) and pro-apoptosis proteins (Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax)) were determined by Western blotting. In this study, PC-3 cells were more resistant to gemcitabine administration than DU145 cells, which correlated with the higher expression levels of maspin observed in PC-3 cells. Furthermore, maspin knockdown enhanced gemcitabine-induced cell death, as evidenced by the increased number of apoptotic cells. Gemcitabine treatment upregulated the levels of anti-apoptosis proteins (Mcl-2 and Bcl-2) in both scrambled control and maspin-KD cells; however, the fold changes in Mcl-1 and Bcl-2 expression were larger in gemcitabine-treated scrambled control cells than in maspin-KD cells. Finally, our findings indicate for the first time that maspin may mediate the therapeutic efficacy of gemcitabine in HIPC. Our results demonstrate that maspin knockdown enhanced the sensitivity of androgen-independent prostate cancer cells to gemcitabine. Therefore, combining gemcitabine with a drug that targets maspin might constitute a valuable strategy for prostate cancer treatment.

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Acknowledgments

This study was supported by a grant from Taipei Medical University—Shuang Ho Hospital (104TMU-SHH-08).

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    Authors and Affiliations

    1. Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

      Chien-Yu Huang & Ming-Te Huang

    2. Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

      Chien-Yu Huang

    3. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

      Yu-Jia Chang & Ming-Te Huang

    4. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

      Yu-Jia Chang, Batzorig Uyanga & Ming-Te Huang

    5. Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

      Yu-Jia Chang & Ming-Te Huang

    6. Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

      Yu-Jia Chang

    7. Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan and Chang Gung University College of Medicine, Kaohsiung, Taiwan

      Sheng-Dean Luo

    8. Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

      Feng-Yen Lin & Cheng-Jeng Tai

    9. Division of Cardiology, Taipei Medical University Hospital, Taipei, Taiwan

      Feng-Yen Lin

    10. Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan

      Cheng-Jeng Tai

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    1. Chien-Yu Huang
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    Correspondence to Cheng-Jeng Tai or Ming-Te Huang.

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    Chien-Yu Huang and Yu-Jia Chang contributed equally to this work.

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    Huang, CY., Chang, YJ., Luo, SD. et al. Maspin mediates the gemcitabine sensitivity of hormone-independent prostate cancer. Tumor Biol. 37, 4075–4082 (2016). https://doi.org/10.1007/s13277-015-4083-x

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    • DOI: https://doi.org/10.1007/s13277-015-4083-x

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