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

Ming Hsien Chien, Tzong Huei Lee, Wei Jiunn Lee, Yen Hsiu Yeh, Tsai Kun Li, Po Chuan Wang, Jih Jung Chen, Jyh Ming Chow, Yung Wei Lin, Michael Hsiao, Shih Wei Wang, Kuo Tai Hua

研究成果: 雜誌貢獻文章

6 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)249-261
頁數13
期刊Cancer Letters
388
DOIs
出版狀態已發佈 - 三月 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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