Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells.
Dietary polyphenols have been correlated with a reduced risk of developing cancer. Quercetin (a natural polyphenolic compound) induced apoptosis in many human cancer cell lines, including breast cancer MCF-7 cells. However, the involvement of possible signaling pathways and the roles of quercetin in apoptosis are still undefined. The purpose of this study was to investigate the effects of quercetin on the induction of the apoptotic pathway in human breast cancer MCF-7 cells. When MCF-7 cells were treated with quercetin for 24 and 48 h and at various doses (10-175 microM), cell viability decreased significantly in time- and dose-dependent manners. Exposure of MCF-7 cells to 10-175 microM quercetin resulted in an approximate 90.25% decrease in viable cells. To explicate the mechanism underlying the antiproliferative effect of quercetin, cell cycle distribution and apoptosis in MCF-7 cells was investigated after exposure to 150 microM quercetin for 6-48 h. Quercetin caused a remarkable increase in the number of S phase (14.56% to 61.35%) and sub-G1 phase cells (0.1% to 8.32%) in a dose- and time-dependent manner. Quercetin caused S phase arrest by decreasing the protein expression of CDK2, cyclins A and B while increasing the p53 and p57 proteins. Following incubation with quercetin for 48 h, MCF-7 cells showed apoptotic cell death by the decreased levels of Bcl-2 protein and DeltaPsi(m) and increased activations of caspase-6, -8 and -9. Moreover, quercetin increased the AIF protein released from mitochondria to nuclei and the GADD153 protein translocation from endoplasmic reticulum to the nuclei. These data suggested that quercetin may induce apoptosis by direct activation of the caspase cascade through the mitochondrial pathway in MCF-7 cells.
Chou
Chu-Chung
CC
Cancer Research Center, Department of Medical Research, Changhua Christian Hospital, Changhua, 500, Taiwan.
Yang
Jai-Sing
JS
Lu
Hsu-Feng
HF
Ip
Siu-Wan
SW
Lo
Chyi
C
Wu
Chih-Chung
CC
Lin
Jing-Pin
JP
Tang
Nou-Ying
NY
Chung
Jing-Gung
JG
Chou
Ming-Jen
MJ
Teng
Ying-Hock
YH
Chen
Dar-Ren
DR
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000187:drug effects / Q000378:metabolism
C494829:AIFM1 protein, human; D000972:Antineoplastic Agents, Phytogenic; D051033:Apoptosis Inducing Factor; C497249:DDIT3 protein, human; D051742:Transcription Factor CHOP; D011794:Quercetin; D020169:Caspases