title: Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells.
abstract: Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent anti-tumor activity. Recently, triptolide was found to induce autophagy in cancer cells. However, the effects of triptolide on autophagy in human prostate cancer (PCa) cells have not yet been clearly elucidated. In this study, we demonstrated that triptolide induces autophagy in three PCa cell lines, PC-3, LNCaP and C4-2. Furthermore, we found that triptolide mediates intracellular accumulation of free calcium by stimulating the endoplasmic reticulum (ER) stress response. This activates the CaMKKβ-AMPK signaling pathway, which in turn inhibits mTOR and activates both ULK1 and Beclin 1, finally resulting in autophagy. Moreover, we found that treatment with autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhances triptolide-induced PCa cell death and growth inhibition. Using a PC-3-xenografted mouse model, we showed that blocking autophagy with CQ significantly promoted triptolide-induced tumor growth inhibition in vivo. Overall, our results show that triptolide induces protective autophagy through the CaMKKβ-AMPK pathway in PCa cells, implying that a combination of triptolide with autophagy inhibitors may potentially be an effective therapeutic strategy for PCa.
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Huang
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China.|State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Mao
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China.|State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China.|Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010616:Phenanthrenes / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D012333:RNA, Messenger; C001899:triptolide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases
keywords: AMPK; CaMKKβ; apoptosis; autophagy; triptolide