title: Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts.
abstract: Pancreatic cancer is an aggressive malignancy, which generally responds poorly to chemotherapy. In this study, trichodermin, an endophytic fungal metabolite from Nalanthamala psidii, was identified as a potent and selective antitumor agent in human pancreatic cancer. Trichodermin exhibited antiproliferative effects against pancreatic cancer cells, especially p53-mutated cells (MIA PaCa-2 and BxPC-3) rather than normal pancreatic epithelial cells. We found that trichodermin induced caspase-dependent and mitochondrial intrinsic apoptosis. Trichodermin also increased apoptosis through mitotic arrest by activating Cdc2/cyclin B1 complex activity. Moreover, trichodermin promoted the activation of c-Jun N-terminal kinase (JNK), and inhibition of JNK by its inhibitor, shRNA, or siRNA significantly reversed trichodermin-mediated caspase-dependent apoptosis. Trichodermin triggered DNA damage stress to activate p53 function for executing apoptosis in p53-mutated cells. Importantly, we demonstrated that trichodermin with efficacy similar to gemcitabine, profoundly suppressed tumor growth through inducing intratumoral DNA damage and JNK activation in orthotopic pancreatic cancer model. Based on these findings, trichodermin is a potential therapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially the mutant p53 pancreatic cancer.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
authors.affiliation: Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Tzong-Huei
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yen-Hsiu
authors.initials: YH
authors.lastname: Yeh
authors.affiliation: Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan.
authors.forename: Po-Chuan
authors.initials: PC
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: Jih-Jung
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jyh-Ming
authors.initials: JM
authors.lastname: Chow
authors.affiliation: Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yung-Wei
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan. Electronic address: shihwei@mmc.edu.tw.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: kthua@ntu.edu.tw.
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D014243:Trichodermin / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D014243:Trichodermin; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Apoptosis; DNA damage; Mitotic arrest; Pancreatic cancer; Trichodermin; c-Jun N-terminal kinase