Triptolide inactivates Akt and induces caspase-dependent death in cervical cancer cells via the mitochondrial pathway.
Triptolide, the main active component of the traditional Chinese herbal medicine Tripterygium wilfordii Hook F, has been shown to have potent immunosuppressive and anti-inflammatory properties. Here, we investigated the pro-apoptotic effect of triptolide in human cervical cancer cells and its underlying mechanisms. Exposure of cervical cancer cells to triptolide induced apoptosis, which was accompanied by loss of mitochondrial membrane potential, caspase processing (caspase-8, -9 and -3), and cleavage of the caspase substrate, poly(ADP-ribose) polymerase. The cytotoxic effects of triptolide were significantly inhibited by the caspase inhibitor, z-VAD-fmk. Triptolide-induced apoptosis was associated with a marked reduction in Akt phosphorylation and was exacerbated by LY294002 (phosphatidylinositol-3'-kinase inhibitor). Conversely, it was attenuated by Akt overexpression. Triptolide-induced apoptosis was also associated with downregulation of Mcl-1 and was significantly inhibited by Mcl-1 overexpression. These findings show that triptolide induces caspase-dependent, mitochondria-mediated apoptosis in cervical cancer cells, in part, by negatively regulating Akt and Mcl-1.
Kim
Min Jung
MJ
Shinsegae Women's Hospital, Busan, Korea.
Lee
Tae Hwa
TH
Kim
Sung Han
SH
Choi
Yeon-Joo
YJ
Heo
Jeonghoon
J
Kim
Young-Ho
YH
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D053938:DNA Fragmentation; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010616:Phenanthrenes / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010616:Phenanthrenes; D019253:Proto-Oncogene Proteins c-bcl-2; C001899:triptolide; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases