Role of Bax in quercetin-induced apoptosis in human prostate cancer cells.
The aim of this study was to investigate the effect of quercetin, a flavonoid, on the apoptotic pathway in a human prostate cell line (LNCaP). We observed that treatment of cells for 24h with quercetin-induced cell death in a dose-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in quercetin-treated cells. Treatment of LNCaP cells with an apoptosis inducing concentration of quercetin (100 microM) resulted in a rapid decrease in the inhibitory Ser473 phosphorylation of Akt leading to inhibition of its kinase activity. Quercetin treatment (100 microM) also caused a decrease in Ser136 phosphorylation of Bad, which is a downstream target of Akt. Protein interaction assay revealed that during treatment with quercetin, Bcl-xL dissociated from Bax and then associated with Bad. Our results also show that quercetin decreases the Bcl-xL:Bax ratio and increases translocation and multimerization of Bax to the mitochondrial membrane. The translocation is accompanied by cytochrome c release, and procaspases-3, -8 and -9 cleavage and increased poly(ADP-ribose) polymerase (PARP) cleavage. Similar results were observed in human colon cancer HCT116Bax+/+ cell line, but not HCT116Bax-/- cell line. Interestingly, at similar concentrations (100 microM), quercetin treatment did not affect the viability or rate of apoptosis in normal human prostate epithelial cell line (PrEC) and rat prostate epithelial cell line (YPEN-1). Our results indicate that the apoptotic processes caused by quercetin are mediated by the dissociation of Bax from Bcl-xL and the activation of caspase families in human prostate cancer cells.
Lee
Dae-Hee
DH
Department of Surgery and Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. leeyj@upmc.edu
Szczepanski
Miroslaw
M
Lee
Yong J
YJ
D017304:Annexin A5 / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D017304:Annexin A5; D016588:Anticarcinogenic Agents; C494819:BAD protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D011794:Quercetin; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases