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.

GSH/GSSG redox couple plays central role in aryl hydrocarbon receptor‐dependent modulation of cytochrome P450 1A1

“…In this study, we have found that up‐regulation of CYP1A1 required relatively reducing conditions as shown by measurement of cellular GSH/GSSG ratio and redox state which was in correlation with CYP1A1 transcription and enzyme activities in vivo and in vitro. Down‐regulation of CYP1A1 by oxidants has been reported earlier in several studies . We and the other researchers have shown that CYP1A1 can be down‐regulated under oxidative stress conditions .…”

6‐Formylindolo[3,2‐b]carbazole reduces apoptosis induced by benzo[a]pyrene in a mitochondrial‐dependent manner

“…Moreover, mulberry extracts were found to impair the skin damage induced by B[a]P through the inhibition of the AhR signaling (Woo, Lee, Park, & Jung, 2017). As a compound, FICZ plays a bifunctional role in cell growth and apoptosis, which depends heavily on its concentration and cell type (Mohammadi‐Bardbori et al, 2017). A high concentration of FICZ (such as 1 µM) can induce sustained CYP1A1 activity and trigger a cascade of cellular events.…”

Aryl hydrocarbon‐estrogen alpha receptor‐dependent expression of miR‐206, miR‐27b, and miR‐133a suppress cell proliferation and migration in MCF‐7 cells

“…The fact that the discovery of the endogenous AhR ligand and FICZ treatment led to the overexpression of miR‐206, miR‐133a, and miR‐27b in an AhR‐dependent manner is new in this study (Figure ). In our previous study, we showed that by increasing the levels of the endogenous ligand FICZ, CYP1A1 inhibitors change cell growth kinetics and trigger apoptosis through a mitochondrial‐dependent pathway . miR‐27b‐3p interacts with the 3′‐untranslated region of cytochrome P450 1B1 (CYP1B1) and the product of this enzyme is assumed to be involved in the metabolic activation of procarcinogens .…”

“…FICZ has been shown to play an important role in several physiological pathways, such as the modulation of the immune system, regulation of circadian rhythms, and skin homeostasis . In addition, FICZ in a regulatory feedback mechanism, which can be efficiently metabolized by the cytochrome P450 family 1 enzymes, especially CYP1A1, CYP1A2, and CYP1B1 . Some of the most important enzymes under the regulatory control of AhR are CYP1A1 and CYP1B1, which catalyze the metabolic activation of 17β‐estradiol (E2) at the C‐2 and C‐4 positions, respectively .…”