Shikonin targets cytosolic thioredoxin reductase to induce ROS-mediated apoptosis in human promyelocytic leukemia HL-60 cells |
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| Affiliation: | 1. Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China;2. Department of Central Laboratory of Blood Cancer, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China;1. College of Life Sciences & Biotechnology, Korea University, 5-1 Anam-dong, Seongbuk-gu, Seoul 136-701, Republic of Korea;2. Department of Microbiology, College of Medicine, Korea University, 5-1 Anam-dong, Seongbuk-gu, Seoul 136-701, Republic of Korea;3. Department of Molecular & Cellular Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 108, Houston, TX, USA;1. Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia;2. Tissue Organ Bank & Tissue Engineering Centre, General Hospital of Ningxia Medical University, Ningxia, China;3. Cancer Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia;4. Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China;1. Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India;2. Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India;1. School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland;2. Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus;3. Centre of Chromosome Biology, Biochemistry, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland;1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea;2. Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea;3. Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea;4. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA |
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| Abstract: | Shikonin, a major active component of the Chinese herbal plant Lithospermum erythrorhizon, has been applied for centuries in traditional Chinese medicine. Although shikonin demonstrates potent anticancer efficacy in numerous types of human cancer cells, the cellular targets of shikonin have not been fully defined. We report here that shikonin may interact with the cytosolic thioredoxin reductase (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme with a C-terminal -Gly-Cys-Sec-Gly active site, to induce reactive oxygen species (ROS)-mediated apoptosis in human promyelocytic leukemia HL-60 cells. Shikonin primarily targets the Sec residue in TrxR1 to inhibit its physiological function, but further shifts the enzyme to an NADPH oxidase to generate superoxide anions, which leads to accumulation of ROS and collapse of the intracellular redox balance. Importantly, overexpression of functional TrxR1 attenuates the cytotoxicity of shikonin, whereas knockdown of TrxR1 sensitizes cells to shikonin treatment. Targeting TrxR1 with shikonin thus discloses a previously unrecognized mechanism underlying the biological activity of shikonin and provides an in-depth insight into the action of shikonin in the treatment of cancer. |
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| Keywords: | Thioredoxin reductase Shikonin Reactive oxygen species Redox Apoptosis Free radicals |
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