Phosphorylation of p53, induction of Bax and activation of caspases during beta-lapachone-mediated apoptosis in human prostate epithelial cells.
The DNA topoisomerase I inhibitor beta-lapachone, the product of a tree from South America, is known to exhibit various biological properties, the mechanisms of which are poorly understood. We investigated the effects of beta-lapachone on the growth of human prostate epithelial cells. Upon treatment with beta-lapachone, a concentration-dependent inhibition of cell viability was observed and cells developed many of the hallmark features of apoptosis, including condensation of chromatin and DNA fragmentation. The apoptotic effects of beta-lapachone were associated with marked induction of p53 phosphorylation and Bax protein without altering the expression of p53 and Bcl-2 protein. In addition, the proteolytic cleavage of specific target proteins such as poly(ADP-ribose) polymerase, beta-catenin and Rad51, which are hallmarks of apoptosis, were observed, and Western blotting demonstrated that processing/activation of caspases release cytochrome c from the mitochondria into the cytosol and accompany the generation of beta-lapachone-mediating apoptotic cell death. However, beta-lapachone did not affect the levels of c-IAP family proteins. The present results suggest that apoptotic signals evoked by beta-lapachone in human prostate epithelial cells may converge caspases activation through up-regulation of phosphorylation of p53 and Bax rather than down-regulation of c-IAPs family.
Choi
Yung Hyun
YH
Department of Biochemistry, Dong-Eui University College of Oriental Medicine and Research Center for Oriental Medicine, Pusan 614-052, Korea. choiyh@dongeui.ac.kr
Kim
Mi Jung
MJ
Lee
Seung Yeon
SY
Lee
Youl-Nam
YN
Chi
Gyoo Yong
GY
Eom
Hyun Sup
HS
Kim
Nam Deuk
ND
Choi
Byung Tae
BT
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051135:Rad51 Recombinase; D059004:Topoisomerase I Inhibitors; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D051176:beta Catenin
D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; C495270:CTNNB1 protein, human; D003574:Cytochrome c Group; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D059004:Topoisomerase I Inhibitors; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; C014638:beta-lapachone; D011065:Poly(ADP-ribose) Polymerases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D020169:Caspases