title: Induction of reactive oxygen species generation inhibits epithelial-mesenchymal transition and promotes growth arrest in prostate cancer cells.
abstract: Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis.
authors.affiliation: Center of Excellence in Cancer Research, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas.
authors.forename: Trinath P
authors.initials: TP
authors.lastname: Das
authors.forename: Suman
authors.initials: S
authors.lastname: Suman
authors.forename: Chendil
authors.initials: C
authors.lastname: Damodaran
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002374:Catalase / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003374:Coumarins / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009361:Neoplasm Invasiveness; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013482:Superoxide Dismutase / Q000096:biosynthesis; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D000111:Acetylcysteine; D000975:Antioxidants; D001572:Benzofurans; D015820:Cadherins; D053148:Caspase 3; D053453:Caspase 9; D002374:Catalase; D003374:Coumarins; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D017382:Reactive Oxygen Species; D000071250:Snail Family Transcription Factors; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors; D051176:beta Catenin; D000099156:Superoxide Dismutase 2; C000604407:SNAI1 protein, human; C000606290:SOD1 protein, human; C102768:psoralidin
keywords: apoptosis; dietary agents; invasion; migration