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EGFR mediates docetaxel resistance in human castration-resistant prostate cancer through the Akt-dependent expression of ABCB1 (MDR1)

  • Molecular Toxicology
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Abstract

Recent studies have shown that docetaxel-based chemotherapy confers a survival benefit in patients with castration-resistant prostate cancer (PC). Also epidermal growth factor receptor (EGFR) was found to have multiple roles in prostatic tumorigenesis. However, the EGFR-mediated chemoresistance mechanism in human PC was not well delineated. In this study, we explored the mechanism of EGFR-mediated docetaxel resistance in PC. A series of stable docetaxel-resistant PC/DX sublines were established at our laboratory. The docetaxel IC50s of PC3 and PC/DX25 cells were 0.01 and 1.33 μM, respectively. Cellular resistance to docetaxel was significantly associated with increased EGFR and EGFR activation in PC/DX25. There was a dose-dependent increase in EGFR expression associated with the magnitude of docetaxel resistance. Expression of EGFR in PC/DX25 was higher than that in PC3, RWPE-1 and LNCaP cells. Similar results were also found in human PC tissues by immunohistochemical staining. We showed that docetaxel sensitivity can be stored in PC/DX25 cells by knockdown and inactivation of EGFR expression through EGFR siRNA and specific inhibitors, respectively. Contrarily, overexpression of EGFR or recombinant EGF protein treatment could rescue PC3 cells from docetaxel-mediated cytotoxicity. Gefitninb (ZD1839) significantly inhibited the growth of PC/DX25 cells by MTT in vitro and on xenografted nude mice in vivo. Moreover, EGFR-mediated docetaxel resistance occurred through the Akt-dependent ABCB1 expression in PC cells. These findings demonstrated EGFR played an important role in docetaxel-resistant PC and EGFR inhibition may enhance the therapeutic efficacy of docetaxel-based treatment.

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Acknowledgments

Special thanks to Dr. Long-Yuan Li (Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan), who kindly provided the full-length EGFR expressing plasmid in this study, as well as Dr. Hua-Chien Chen and Dr. Shu-Jen Chen (Department of Life Science, Chang Gung University, Tao-Yuan, Taiwan) for their excellent technical assistances of cDNA microarray. This study is funded by National Science Council, Executive Yuan, Taiwan (Grant No. NSC96-2314-B-037-010, NSC 101-2314-B-037-008-MY3 and NSC99-2314-B-037-020-MY3) and Far Eastern Memorial Hospital, New Taipei City, Taiwan (Grant No. FEMH-2012-C-009).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan

    Tzyh-Chyuan Hour, Shu-Ju Chuang & A-Mei Huang

  2. Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan

    Shiu-Dong Chung

  3. Department of Pathology, Kuo General Hospital, Tainan, Taiwan

    Wang-Yi Kang

  4. Faculty of Dentistry, Kaohsiung Medical University, Kaohsiung, Taiwan

    Ying-Chu Lin

  5. Department of Urology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Wen-Jeng Wu & Shu-Pin Huang

  6. Department of Urology, National Taiwan University Hospital and College of Medicine, National Taiwan University, 7 Chung-Shan South Road, Taipei, 100, Taiwan

    Chao-Yuan Huang & Yeong-Shiau Pu

  7. School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

    Shiu-Dong Chung

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  1. Tzyh-Chyuan Hour
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Correspondence to Chao-Yuan Huang or Yeong-Shiau Pu.

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Hour, TC., Chung, SD., Kang, WY. et al. EGFR mediates docetaxel resistance in human castration-resistant prostate cancer through the Akt-dependent expression of ABCB1 (MDR1). Arch Toxicol 89, 591–605 (2015). https://doi.org/10.1007/s00204-014-1275-x

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  • DOI: https://doi.org/10.1007/s00204-014-1275-x

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