Triptolide inhibits Jak2 transcription and induces apoptosis in human myeloproliferative disorder cells bearing Jak2V617F through caspase-3-mediated cleavage of Mcl-1.
The discovery of oncogene addiction in myeloproliferative disorders (MPDs) driven by the gain-of-function mutant Jak2V617F has attracted intense interest in targeted therapy for MPDs. In this report, we demonstrate that triptolide potently downregulated the transcription of Jak2 by inhibiting the activity of RNA polymerase. Triptolide inhibited the in vitro and in vivo growth of tumor cells harboring Jak2V617F. Triptolide induced abundant apoptosis with a prominent decline of Bcl-2, Bcl-X(L), survivin and Mcl-1. As well, triptolide induced caspase-3-dependent Mcl-1 cleavage, which may potentiate apoptosis. These findings suggest that triptolide is a promising agent to kill Jak2V617F-harboring cells.
Chen
Qi
Q
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China.
Lu
Zhongzheng
Z
Jin
Yanli
Y
Wu
Yongbin
Y
Pan
Jingxuan
J
D019943:Amino Acid Substitution; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010616:Phenanthrenes / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D017931:DNA Primers; D004224:Diterpenes; D004852:Epoxy Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010616:Phenanthrenes; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C001899:triptolide; D003513:Cycloheximide; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053148:Caspase 3