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Glucose-regulated protein 78 mediates the anticancer efficacy of shikonin in hormone-refractory prostate cancer cells

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Tumor Biology

Abstract

Glucose-regulated protein 78 (GRP78) is a key modulator of prostate cancer progression and therapeutic resistance. Prostate cancer is a worldwide health problem, and therapeutic resistance is a critical obstacle for the treatment of hormone-refractory prostate cancer patients. Shikonin inhibits prostate cancer proliferation and metastasis. However, the role of GRP78 in the cytotoxic effect of shikonin in prostate cancer cells remains unclear. GRP78 expression was abolished using small interfering RNA (siRNA), and the anticancer effects of shikonin were assessed using MTT assays, the XCELLigence biosensor, flow cytometric cell cycle analysis, and Annexin V-PI apoptotic assays. PC-3 cells expressed more GRP78 than DU-145 cells, and the MTT assays revealed that DU-145 cells were more sensitive to shikonin than PC-3 cells. GRP78 knockdown (GRP78KD) PC-3 cells were more sensitive to shikonin treatment than scrambled siRNA control cells. Based on cell cycle analysis and AnnexinV-PI apoptotic assays, apoptosis dramatically increased in GRP78KD cells compared with the control PC-3 in response to shikonin. Finally, in response to shikonin treatment, Mcl-1 and Bcl-2 levels increased in the scrambled control cells treated with shikonin, whereas Bcl-2 decreased and Mcl-1 slightly increased in the GRP78KD PC-3 cells. The levels of Bax and Bad did not change in the scrambled control or GRP78KD cells after shikonin treatment. These results are consistent with the increased sensitivity to shikonin after knockdown of GRP78. GRP78 expression may determine the therapeutic efficacy of shikonin against prostate cancer cells.

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Acknowledgments

This study was supported by grants from the Taipei Medical University and Taipei Medical University Hospital (101TMU-TMUH-01-2) and National Science council(NSC101-2314-B-038-016-MY3).

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Author notes

    Authors and Affiliations

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

      Li-Jen Kuo & Yu-Jia Chang

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

      Li-Jen Kuo, Chin-Sheng Hung, Yu-Jia Chang & Ming-Te Huang

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

      Li-Jen Kuo, Chin-Sheng Hung & Yu-Jia Chang

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

      Yu-Jia Chang

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

      Chien-Yu Huang & Ming-Te Huang

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

      Chien-Yu Huang

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

      Wan-Li Cheng & Feng-Yen Lin

    8. Department of Urology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan

      Chun-Te Wu

    9. 250 Wu-Xin Street, Taipei City, Taiwan, 110

      Yu-Jia Chang & Ming-Te Huang

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    Correspondence to Yu-Jia Chang or Ming-Te Huang.

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    Li-Jen Kuo and Chien-Yu Huang contributed equally to this work.

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    Kuo, LJ., Huang, CY., Cheng, WL. et al. Glucose-regulated protein 78 mediates the anticancer efficacy of shikonin in hormone-refractory prostate cancer cells. Tumor Biol. 36, 5063–5070 (2015). https://doi.org/10.1007/s13277-015-3157-0

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    • DOI: https://doi.org/10.1007/s13277-015-3157-0

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