Effect of pristimerin on apoptosis through activation of ROS/ endoplasmic reticulum (ER) stress-mediated noxa in colorectal cancer |
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| Affiliation: | 1. Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China;2. State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;3. Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China;4. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;1. Department of Chinese Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan;2. Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan Hospital, Taipei, Taiwan;3. Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;4. Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan;5. Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;6. Department of Surgery, China Medical University Hospital, Taichung, Taiwan;7. Department of Surgery, University of Illinois, Chicago, IL, United States;8. Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan;9. School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan;10. Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan;11. School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan;12. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei, Taiwan;1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;2. Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;3. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510510, China |
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| Abstract: | BackgroundPristimerin, a natural quinonemethid triterpenoid found in different spp. of Celastraceae and Hippocrateaceae families, has been reported to exhibit potent antitumor activities against colorectal cancer (CRC). However, the mechanisms underlying pristimerin-induced apoptosis in CRC is not clear.PurposeThis study aimed to investigate the mechanisms of pristimerin-induced apoptosis against CRC in vitro and in vivo.MethodsCell viability and cell apoptosis analyses were conducted to assess the effects of pristimerin on CRC. Western blotting was performed to detect the expression of proteins affected by pristimerin in vitro and in vivo. HCT116 colon cancer xenografts and APCmin/+ mouse models were used to evaluate the anti-CRC effect of pristimerin in vivo.ResultsOur data showed that pristimerin induced apoptosis by regulating proapoptotic proteins of which Noxa showed higher expression. Pristimerin triggered reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress signaling activation. Pristimerin significantly elevated the expression of ER stress-related proteins, resulting in activation of the IRE1α and c-Jun N-terminal kinase (JNK) signal pathway through the formation of the IRE1α-TRAF2-ASK1 complex. Pristimerin exhibited apoptosis-inducing activities in HCT116 colon cancer xenografts and APCmin/+ mice.ConclusionBoth in vitro and in vivo data demonstrated that pristimerin induced Noxa expression and apoptosis through activation of the ROS/ER stress/JNK axis in CRC. Thus, pristimerin may be a promising antitumor agent for CRC. |
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