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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

  • Molecular Toxicology
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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.

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Acknowledgements

The authors of this manuscript wish to express their appreciation to Agneta Rannug at Karolinska Instiutet, Stockholm, Sweden, for scientific discussions and suggestions and to Shiraz University of Medical Sciences, Shiraz, Iran. This work was supported by the Research Grants from the Shiraz University of Medical Sciences, Iran, (Grant Numbers 93-01-36-8817; 93-01-36-8818).

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  1. Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

    Afshin Mohammadi-Bardbori, Farzaneh Bastan & Amin-Reza Akbarizadeh

  2. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    Afshin Mohammadi-Bardbori

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  1. Afshin Mohammadi-Bardbori
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  2. Farzaneh Bastan
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Correspondence to Afshin Mohammadi-Bardbori.

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Mohammadi-Bardbori, A., Bastan, F. & Akbarizadeh, AR. 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. Arch Toxicol 91, 3365–3372 (2017). https://doi.org/10.1007/s00204-017-1950-9

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