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The role of TXNDC5 in castration-resistant prostate cancer—involvement of androgen receptor signaling pathway

Oncogene volume 34, pages 4735–4745 (2015)Cite this article

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Abstract

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and the mechanisms behind it remain unclear. Thioredoxin domain-containing protein 5 (TXNDC5) is involved in protein folding and chaperone activity, and its overexpression has been reported in multiple malignancies. In the current study, we demonstrated that TXNDC5 is up-regulated following long-term androgen-deprivation treatment (ADT) and is highly overexpressed in CRPC tumors compared with hormone-naive prostate cancer (PCa) cases. Functionally, in vitro and in vivo studies demonstrated that TXNDC5 overexpression promotes the growth of both androgen-dependent and castration-resistant PCa xenografts. Mechanistically, TXNDC5 directly interacts with the AR protein to increase its stability and thus enhances its transcriptional activity. TXDNC5-mediated CRPC growth can be fully abolished by AR inhibition, suggesting TXDNC5 up-regulation as an escape pathway for aberrant AR re-activation and CRPC growth in the milieu of low androgen. Indeed, we found that TXNDC5 is increased by ADT-induced hypoxia through HIF-1α in an miR-200b-dependent manner. Overall, we defined an important role of TXNDC5 in CRPC and further investigations are needed to screen TXNDC5 antagonists as a novel therapeutic approaches to treat PCa patients with CRPC.

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Acknowledgements

We thank Professor Yaoqin Gong and Professor Huiqing Yuan from Shandong University Medical School for their critical reading of the manuscript. AR expression and PSA-Luc vectors were kindly provided by Professor Huiqing Yuan. This work was supported by the National Natural Science Foundation of China (Grant No.81302239 and No.81300426) and the Foundation for Scientific and Technological Achievements of Jinan (Grant No.201302046).

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Authors and Affiliations

  1. Department of Pathology, Shandong University Medical School, Jinan, China

    L Wang, W Tan, Z Liu, M Qi & B Han

  2. Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China

    L Wang & J Pan

  3. Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China

    G Song

  4. Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China

    X Chang

  5. Shandong institute of medicine and health informations, Jinan, China

    X Zhu

  6. Department of Pathology, Shandong University Qilu hospital, Jinan, China

    Z Liu & B Han

  7. Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    J Yu

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  1. L Wang
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Correspondence to B Han.

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Wang, L., Song, G., Chang, X. et al. The role of TXNDC5 in castration-resistant prostate cancer—involvement of androgen receptor signaling pathway. Oncogene 34, 4735–4745 (2015). https://doi.org/10.1038/onc.2014.401

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  • DOI: https://doi.org/10.1038/onc.2014.401

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