Interleukin-6 selectively induces drug metabolism to potentiate the genotoxicity of dietary carcinogens in mammary cells
File(s)
Published version
Author(s)
Malik, Durr-e-Shahwar
David, Rhiannon
Gooderham, Nigel
Type
Journal Article
Abstract
Breast cancer is the most commonly diagnosed malignancy in females, the aetiology being
multifactorial and includes the role of lifestyle exposure to DNA damaging chemicals such as
dietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b]
pyridine (PhIP). Both compounds require cytochrome P450 (CYP) mediated metabolic activation
to DNA damaging species, and both induce transcriptional responses through the nuclear
receptors Aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα). BaP and PhIP are
mammary carcinogens in rodents. Clinically, circulating IL-6 expression is linked with poor
prognosis of cancer and 35% of the deaths in breast cancer are linked with inflammation. The
objective of this work was to investigate the molecular toxicology and local activation of BaP and
PhIP in the presence of IL-6. Our laboratory has previously reported that miR27b can regulate
CYP1B1 expression in colorectal cells, here we have investigated if this mechanism is working in
mammary cell models, MCF-7 and MDA-MB-231 cells. Treatment (24h) of cells with BaP (10nM10µM) and PhIP (100nM-100µM) significantly induced genetic damage (micronuclei formation) in
a dose dependent manner in both cell lines. This effect was potentiated in the presence human
IL-6 at concentrations reported to be expressed in clinical breast cancer. On its own, IL-6
treatment failed to induce micronuclei frequency above control levels in these cells. Compared to
BaP or PhIP treatment alone, IL-6 plus BaP or PhIP, selectively induced CYP1B1 significantly in
both cell lines. Additionally, miR27b expression was downregulated by IL-6 treatments and
transfection with miR27b inhibitor confirmed that miR27b is a regulator of CYP1B1 in both cell
lines. These data show that BaP- and PhIP-induced DNA damage in mammary cells is potentiated
by the inflammatory cytokine IL-6 and that inflammation-induced CYP expression, specifically
CYP1B1 via miR27b, is responsible for this effect.
multifactorial and includes the role of lifestyle exposure to DNA damaging chemicals such as
dietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b]
pyridine (PhIP). Both compounds require cytochrome P450 (CYP) mediated metabolic activation
to DNA damaging species, and both induce transcriptional responses through the nuclear
receptors Aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα). BaP and PhIP are
mammary carcinogens in rodents. Clinically, circulating IL-6 expression is linked with poor
prognosis of cancer and 35% of the deaths in breast cancer are linked with inflammation. The
objective of this work was to investigate the molecular toxicology and local activation of BaP and
PhIP in the presence of IL-6. Our laboratory has previously reported that miR27b can regulate
CYP1B1 expression in colorectal cells, here we have investigated if this mechanism is working in
mammary cell models, MCF-7 and MDA-MB-231 cells. Treatment (24h) of cells with BaP (10nM10µM) and PhIP (100nM-100µM) significantly induced genetic damage (micronuclei formation) in
a dose dependent manner in both cell lines. This effect was potentiated in the presence human
IL-6 at concentrations reported to be expressed in clinical breast cancer. On its own, IL-6
treatment failed to induce micronuclei frequency above control levels in these cells. Compared to
BaP or PhIP treatment alone, IL-6 plus BaP or PhIP, selectively induced CYP1B1 significantly in
both cell lines. Additionally, miR27b expression was downregulated by IL-6 treatments and
transfection with miR27b inhibitor confirmed that miR27b is a regulator of CYP1B1 in both cell
lines. These data show that BaP- and PhIP-induced DNA damage in mammary cells is potentiated
by the inflammatory cytokine IL-6 and that inflammation-induced CYP expression, specifically
CYP1B1 via miR27b, is responsible for this effect.
Date Issued
2019-10
Date Acceptance
2019-09-02
Citation
Archives of Toxicology, 2019, 93 (10), pp.3005-3020
ISSN
0340-5761
Publisher
Springer (part of Springer Nature)
Start Page
3005
End Page
3020
Journal / Book Title
Archives of Toxicology
Volume
93
Issue
10
Copyright Statement
© The Author(s) 2019
Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Subjects
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Benzo(a)pyrene
Genotoxicity
Human mammary cells
IL-6
Inflammation
miRNA
Toxicology
1115 Pharmacology and Pharmaceutical Sciences
Publication Status
Published
Date Publish Online
2019-09-12