title: NF-κB plays a key role in microcystin-RR-induced HeLa cell proliferation and apoptosis.
abstract: Microcystins (MCs) are well-known cyanobacterial toxins produced in eutrophic waters and can act as potential carcinogens and have caused serious risk to human health. However, pleiotropic even paradoxical actions of cells exposure to MCs have been reported, and the mechanisms of MC-induced tumorigenesis and apoptosis are still unknown. In this study, we performed the first comprehensive in vitro investigation on carcinogenesis associated with nuclear factor kappa B (NF-κB) and its downstream genes in HeLa cells (Human cervix adenocarcinoma cell line from epithelial cells) exposure to MC-RR. HeLa cells were treated with 0, 20, 40, 60, and 80 µg/mL MC-RR for 4, 8, 12, and 24 h. HeLa cells presented dualistic responses to different doses of MCs. CCK8 assay showed that MC-RR exposure evidently enhanced cell viability of HeLa cells at lower MCs doses. Cell cycle and apoptosis analysis revealed that lower MCs doses promoted G1/S transition and cell proliferation while higher doses of MCs induced apoptosis, with a dose-dependent manner. Electrophoretic mobility shift assay (EMSA) revealed that MC-RR could increase/decrease NF-κB activity at lower/higher MC-RR doses, respectively. Furthermore, the expression of NF-κB downstream target genes including c-FLIP, cyclinD1, c-myc, and c-IAP2 showed the same variation trend as NF-κB activity both at mRNA and protein levels, which were induced by lower doses of MC-RR and suppressed by higher doses. Our data verified for the first time that NF-κB pathway may mediate MC-induced cell proliferation and apoptosis and provided a better understanding of the molecular mechanism for potential carcinogenicity of MC-RR.
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China.
authors.forename: Xuezhen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Fan
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Shangchun
authors.initials: S
authors.lastname: Li
authors.affiliation: Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China. Electronic address: xieping@ihb.ac.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000139:chemically induced; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification
chemical_list: D002273:Carcinogens; D008387:Marine Toxins; D052998:Microcystins; D016328:NF-kappa B; D012313:RNA; D004247:DNA; C063855:microcystin RR
keywords: Apoptosis; Cell proliferation; HeLa cells; Hormesis; Microcystin-RR; NF-κB