title: The roles of endoplasmic reticulum stress and mitochondrial apoptotic signaling pathway in quercetin-mediated cell death of human prostate cancer PC-3 cells.
abstract: Prostate cancer has its highest incidence and is becoming a major concern. Many studies have shown that traditional Chinese medicine exhibited antitumor responses. Quercetin, a natural polyphenolic compound, has been shown to induce apoptosis in many human cancer cell lines. Although numerous evidences show multiple possible signaling pathways of quercetin in apoptosis, there is no report to address the role of endoplasmic reticulum (ER) stress in quercetin-induced apoptosis in PC-3 cells. The purpose of this study was to investigate the effects of quercetin on the induction of the apoptotic pathway in human prostate cancer PC-3 cells. Cells were treated with quercetin for 24 and 48 h and at various doses (50-200 μM), and cell morphology and viability decreased significantly in dose-dependent manners. Flow cytometric assay indicated that quercetin at 150 μM caused G0/G1 phase arrest (31.4-49.7%) and sub-G1 phase cells (19.77%) for 36 h treatment and this effect is a time-dependent manner. Western blotting analysis indicated that quercetin induces the G0/G1 phase arrest via decreasing the levels of CDK2, cyclins E, and D proteins. Quercetin also stimulated the protein expression of ATF, GRP78, and GADD153 which is a hall marker of ER stress. Furthermore, PC-3 cells after incubation with quercetin for 48 h showed an apoptotic cell death and DNA damage which are confirmed by DAPI and Comet assays, leading to decrease the antiapoptotic Bcl-2 protein and level of ΔΨm , and increase the proapoptotic Bax protein and the activations of caspase-3, -8, and -9. Moreover, quercetin promoted the trafficking of AIF protein released from mitochondria to nuclei. These data suggest that quercetin may induce apoptosis by direct activation of caspase cascade through mitochondrial pathway and ER stress in PC-3 cells.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan.
authors.forename: Kuo-Ching
authors.initials: KC
authors.lastname: Liu
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Yen
authors.forename: Rick Sai-Chuen
authors.initials: RS
authors.lastname: Wu
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.forename: Hsu-Feng
authors.initials: HF
authors.lastname: Lu
authors.forename: Kung-Wen
authors.initials: KW
authors.lastname: Lu
authors.forename: Chyi
authors.initials: C
authors.lastname: Lo
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Nou-Ying
authors.initials: NY
authors.lastname: Tang
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Wu
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D017382:Reactive Oxygen Species; D011794:Quercetin; D020169:Caspases; D002118:Calcium