title: Chrysin induces death of prostate cancer cells by inducing ROS and ER stress.
abstract: Chrysin is a natural flavone found in numerous plant extracts, honey, and propolis that has multiple biological activities including anti-cancer effects. Understanding of biological mechanisms mediated in response to chrysin in cancerous cells may provide novel insight into chemotherapeutic approaches with reduced side effects in cancers. In the present study, we investigated functional roles of chrysin in progression of prostate cancer cells using DU145 and PC-3 cell lines. The results showed that chrysin induced apoptosis of cells evidenced by DNA fragmentation and increasing the population of both DU145 and PC-3 cells in the sub-G1phase of the cell cycle. In addition, chrysin reduced expression of proliferating cell nuclear antigen in the prostate cancer cell lines compared to untreated prostate cancer cells. Moreover, chrysin induced loss of mitochondria membrane potential (MMP), while increasing production of reactive oxygen species (ROS) and lipid peroxidation in a dose-dependent manner. Also, it induced endoplasmic reticulum (ER) stress through activation of unfolded protein response (UPR) proteins including PRKR-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), and 78 kDa glucose-regulated protein (GRP78) in DU145 and PC-3 cells. The chrysin-mediated intracellular signaling pathways suppressed phosphoinositide 3-kinase (PI3K) and the abundance of AKT, P70S6K, S6, and P90RSK proteins, but stimulated mitogen-activated protein kinases (MAPK) and activation of ERK1/2 and P38 proteins in the prostate cancer cells. Collectively, these results indicate that chrysin initiates cell death through induction of mitochondrial-mediated apoptosis and ER stress, and regulation of signaling pathways responsible for proliferation of prostate cancer cells.
authors.affiliation: Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Soomin
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.|Department of Biomedical Sciences, Catholic Kwandong University, Gangneung, Republic of Korea.
authors.forename: Whasun
authors.initials: W
authors.lastname: Lim
authors.affiliation: Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, College Station, Texas.
authors.forename: Fuller W
authors.initials: FW
authors.lastname: Bazer
authors.affiliation: Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Gwonhwa
authors.identifier: http://orcid.org/0000-0003-2817-5323
authors.initials: G
authors.lastname: Song
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D005419:Flavonoids; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; C043561:chrysin; D058539:Phosphatidylinositol 3-Kinase; C460640:EIF2AK3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D019892:eIF-2 Kinase; D020928:Mitogen-Activated Protein Kinases
keywords: ER stress; ROS; cell death; chrysin; prostate cancer