title: The highly bioactive molecule and signal substance 6-formylindolo[3,2-b]carbazole (FICZ) plays bi-functional roles in cell growth and apoptosis in vitro.
abstract: The maintenance of cellular homeostasis is a complex process that is governed by the receipt of prototypical growth and death signals. The endogenous functions of aryl hydrocarbon receptor (AHR) in cellular homeostasis are not well understood. We aimed to establish whether the disturbance of endogenously activated AHR can influence cell growth, and if so, what mechanism(s) are involved. Cell growth was measured in mouse hepatoma Hepa-1 wild-type and cytochrome P4501A1 (CYP1A1)-deficient c37 cells. In other sets of experiments, HepG2 cells were exposed to different doses of FICZ (0.01nM-1 µM) alone or in combination with 50 nM of the CYP1A1 inhibitor 3'methoxy-4'nitro-flavone (MNF). CYP1A1 enzyme activity, cell viability, oxidative stress, and several endpoints of apoptosis were measured. FICZ treatment at a high concentration or in combination with MNF induced sustained CYP1A1 activity and led to oxidative stress and activation of apoptosis via a mitochondrial-dependent pathway. In comparison with the wild-type Hepa-1 cells, c37 cells lacking CYP1A1 activity proliferated faster in normal medium which contains trace levels of FICZ. Besides, in HepG2 cells, FICZ stimulated cell growth at low concentrations but inhibited cell growth at high concentrations. Based on these findings, we propose that CYP1A1 inhibitors, by increasing the levels of the endogenous ligand FICZ, change the cell growth kinetics and trigger cell death and apoptosis through a mitochondrial-dependent pathway. Since AHR controls multiple cellular functions, a wide range of toxicity can be expected by disturbing its endogenous functions.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. toxicology@sums.ac.ir.|Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. toxicology@sums.ac.ir.
authors.forename: Afshin
authors.identifier: http://orcid.org/0000-0003-2203-6322
authors.initials: A
authors.lastname: Mohammadi-Bardbori
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Bastan
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Amin-Reza
authors.initials: AR
authors.lastname: Akbarizadeh
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C091768:3'-methoxy-4'-nitroflavone; C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D005419:Flavonoids; D017382:Reactive Oxygen Species; D045304:Cytochromes c; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D005978:Glutathione
keywords: 6-Formylindolo[3,2-b]carbazole (FICZ); Apoptosis; Cell growth; Mitochondrial-dependent pathway