Involvement of p21 and FasL in induction of cell cycle arrest and apoptosis by neochamaejasmin A in human prostate LNCaP cancer cells.
Neochamaejasmin A ( 1), a biflavonoid isolated from the roots of a traditional Chinese medicine, Stellera chamaejasme L., was shown to inhibit cellular (3)H-thymidine incorporation (IC 50 12.5 microg/mL) and subsequent proliferation of human prostate cancer LNCaP cells. Treatment of LNCaP cells with low doses of 1 (< or =6.25 microg/mL) suppressed DNA-binding activities of the transcription factors NFkappaB and AP-1 to the promoter of cyclin D and also inhibited expression of the cell cycle regulatory proteins cyclin D, proliferating cell nuclear antigen, and nucleolin, thus arresting cells in G 1 phase of the cell cycle. A lengthy exposure with higher doses of 1 (> or =12.5 microg/mL) revealed the production of reactive oxygen species, dissipation of the mitochondrial membrane potential, up-regulation of cyclin-dependent kinase inhibitor p21, and induction of cell apoptosis. An aggregation of Fas-procaspase 8-procaspase 3 and p21-procaspase 3 proteins by coimmunoprecipitation, immunoblotting analysis, and MALDI-mass spectrometry indicated the involvement of Fas and p21 in 1-mediated cytotoxicity, and pretreatment of cells with antisense FasL oligonucleotides partially abolished apoptosis. Thus, 1 blocked cell cycle progression at the G 1 phase by activating the p21 protein and ultimately promoting the Fas-caspase 8-caspase 3 apoptotic machinery.
Liu
Wing-Keung
WK
Department of Anatomy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. ken-liu@cuhk.edu.hk
Cheung
Florence W K
FW
Liu
Bonnie P L
BP
Li
Chunman
C
Ye
Wencai
W
Che
Chun-Tao
CT
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D044946:Biflavonoids; D002453:Cell Cycle / Q000187:drug effects*; D056741:Cyclin D; D016213:Cyclins / Q000037:antagonists & inhibitors; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D044946:Biflavonoids; D056741:Cyclin D; D016213:Cyclins; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C530231:neochamaejasmin A