1. Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation
- Author
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George G. Klee, Michael J. Evans, Daniel E. Spratt, Kathryn E. Carnazza, Michael G. Doran, Man Xia Lee, Neel Shah, William R. Polkinghorn, Charles L. Sawyers, Jason S. Lewis, Brian J. Davis, John Wongvipat, and Donald J. Tindall
- Subjects
Male ,Urologic Diseases ,Aging ,Cancer Research ,medicine.medical_treatment ,Blotting, Western ,Oncology and Carcinogenesis ,Fluorescent Antibody Technique ,Mice, SCID ,Biology ,SCID ,Real-Time Polymerase Chain Reaction ,Radiation Tolerance ,Article ,Cell Line ,Androgen ,Androgen deprivation therapy ,Mice ,Prostate cancer ,Downregulation and upregulation ,Cell Line, Tumor ,Radioresistance ,Receptors ,medicine ,Animals ,Humans ,Oncology & Carcinogenesis ,Cancer ,Tumor ,Blotting ,Prostate Cancer ,Prostatic Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,Up-Regulation ,Androgen receptor ,Radiation therapy ,Oncology ,Receptors, Androgen ,Tumor progression ,Luminescent Measurements ,Immunology ,Cancer research ,Comet Assay ,Western - Abstract
Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival. Cancer Res; 75(22); 4688–96. ©2015 AACR.
- Published
- 2015
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