title: Crebanine, an aporphine alkaloid, sensitizes TNF-α-induced apoptosis and suppressed invasion of human lung adenocarcinoma cells A549 by blocking NF-κB-regulated gene products.
abstract: Crebanine is an alkaloid known to exhibit anticancer, but its mechanism is not well understood. Besides, the nuclear factor-kappa B (NF-κB) transcription factor has been correlated with inflammation, carcinogenesis, tumor cell survival, invasion, and angiogenesis. In this study, we investigated the effects of crebanine on tumor necrosis factor alpha (TNF-α)-induced NF-κB activation and the expression of NF-κB-regulated gene products. We found that crebanine reduced the cell proliferation of lung, ovarian, and breast cancer cells. Crebanine also potentiated TNF-α-induced apoptosis which correlated with the suppression of the gene products linked to cell survival, B cell lymphoma-extra large, and proliferation, cyclin D1. In addition, crebanine affected TNF-α-induced activation of caspase-8, caspase-3, and poly(ADP-ribose) polymerase cleavage, indicating that the apoptotic effects of TNF-α were enhanced by crebanine. Moreover, crebanine reduced TNF-α-induced A549 cell invasion and migration. Furthermore, crebanine suppressed the TNF-α-mediated expression of proteins that involved cancer cell invasion (matrix metalloproteinase 9 urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and intercellular adhesion molecule 1) and angiogenesis (COX-2 and VEGF), all of which are known to be regulated by NF-κB. We also demonstrated that TNF-α induced NF-κB DNA-binding activity, which was inhibited by crebanine. Moreover, crebanine suppressed the TNF-α-induced degradation of inhibitor of NF-κB alpha (IκBa), which led to reduced NF-κB translocation to the nucleus. Taken together, our results demonstrated that crebanine reduced TNF-α-induced cancer cell proliferation, invasion, and survival by suppressing NF-κB activity and expression profile of its downstream genes.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Supachai
authors.initials: S
authors.lastname: Yodkeeree
authors.forename: Wilart
authors.initials: W
authors.lastname: Pompimon
authors.forename: Pornngarm
authors.initials: P
authors.lastname: Limtrakul
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001060:Aporphines / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D001060:Aporphines; C494811:BCL2L1 protein, human; D020672:I-kappa B Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D019938:Cyclin D1; C061009:crebanine; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053181:Caspase 8