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. (1st March 2017)

• Record Type: Journal Article
• Authors: Chien, Ming-Hsien; Lee, Tzong-Huei; Lee, Wei-Jiunn; Yeh, Yen-Hsiu; Li, Tsai-Kun; Wang, Po-Chuan; Chen, Jih-Jung; Chow, Jyh-Ming; Lin, Yung-Wei; Hsiao, Michael; Wang, Shih-Wei; Hua, Kuo-Tai
• Is Part Of: Cancer letters. Volume 388(2017)
• Page Start: 249
• Page End: 261
• Publication Date: 2017-03-01
• Subjects: Pancreatic cancer -- Mitotic arrest -- DNA damage -- Apoptosis -- c-Jun N-terminal kinase -- Trichodermin; Bcl-2 B-cell lymphoma 2 -- Bcl-xL B-cell lymphoma extra long -- CDK cyclin-dependent kinase -- Cdc cell division cycle -- DSBs double-strand breaks -- DUSP1 dual specificity protein phosphatase 1 -- IHC immunohistochemical -- JNK c-Jun N-terminal kinase -- Mcl-1 myeloid cell leukemia 1 -- MMP Mitochondrial membrane potential; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.12.002
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Trichodermin exhibits the potent and selective antimitotic antitumor activity against human pancreatic cancer. Trichodermin induces DNA damage stress to activate p53 function for executing apoptosis. JNK activation is pivotal for trichodermin-mediated apoptosis.