HMGB1 release promotes paclitaxel resistance in castration-resistant prostate cancer cells via activating c-Myc expression |
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| Institution: | 1. Division of Cancer Pathobiology, Children''s Hospital of Philadelphia, Philadelphia, PA 19104, USA;2. Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA;3. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA;4. Ludwig Institute for Cancer Research, New York, NY 10017, USA;1. Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran;2. Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;3. Endocrinology and Metabolism Research, and Physiology Research Centers, Kerman University of Medical Sciences, Kerman, Iran;4. Department of Biochemistry, and Metabolism & Endocrinology Research Center, Kerman University of Medical Sciences, Kerman, Iran;5. Neuroscience Research Center, Institute of Neuropharmacology, Kerman Univerity of Medical Sciences, Kerman, Iran;6. Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran |
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| Abstract: | Paclitaxel (PTX) is one of standard chemotherapy drug for patients with metastatic castration-resistant prostate cancer (mCRPC). However, PTX resistance leads to treatment failures, for which the underlying molecular mechanisms remain exclusive. In this study, we reported that PTX-induced constant HMGB1 expression and release confers to PTX resistance in mCRPC cells via activating and sustaining c-Myc signaling. PTX upregulated HMGB1 expression and triggered its release in human mCRPC cells. Silencing HMGB1 by RNAi and blocking HMGB1 release by glycyrrhizin or HMGB1 neutralizing antibody sensitized the response of PTX-resistant mCRPC cells to PTX. Release HMGB1 activated c-Myc expression. Inhibiting c-Myc expression by RNAi or c-MyC inhibitor significantly enhance the sensitivity of PTX-resistant CRPC cells to PTX. Therefore, HMGB1/c-Myc axis is critical in the development of PTX resistance, and targeting HMGB1/c-Myc axis would counteract PTX resistance in mCRPC cells. |
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