Induction of activation-induced cytidine deaminase by a not-directly mutagenic carcinogen: a novel potential molecular mechanism.

Masayuki Tatemichi,Harumi Hata,Toshio Nakadate

doi:10.1007/s12199-014-0382-x

Abstract

The molecular mechanisms underlying the carcinogenic activity of not-directly mutagenic (Ames mutagenicity test-negative) carcinogens are not fully understood. Given recent findings that ectopic expression of activation-induced cytidine deaminase (AID) in somatic cells plays a critical role in carcinogenesis, we investigated whether several of the established not-directly mutagenic carcinogens induce AID expression. We prepared cells with stable expression of luciferase reporter gene containing the promoter of AID. We then used this system to examine the AID promoter activity of the non-genotoxic carcinogen: butyl benzyl phthalate, bisphenol A, di (2-ethylhexyl) phthalate, cadmium chloride (Cd), and butylated hydroxyanisole. Results showed that Cd increased the promoter activity of AID and actually induced AID gene expression. A not-directly mutagenic carcinogen, cadmium, has the potential to induce the AID gene, suggesting that this might represent a novel molecular mechanism of carcinogenesis of cadmium.

Highlights

Most chemical carcinogens are capable of inducing DNA damage and are ‘genotoxic’ in their carcinogenic mode of action
Given recent findings that ectopic expression of activation-induced cytidine deaminase (AID) in somatic cells plays a critical role in carcinogenesis, we investigated whether several of the established not-directly mutagenic carcinogens induce AID expression
Results showed that Cd increased the promoter activity of AID and induced AID gene expression

Summary

Introduction

Most chemical carcinogens are capable of inducing DNA damage and are ‘genotoxic’ in their carcinogenic mode of action. There is, a group of carcinogens that induce cancer in a non-genotoxic manner [1]. A wide variety of molecular mechanisms to explain this cancer induction have been proposed, including receptor-mediated endocrine modulation, non-receptormediated endocrine modulation, tumor-promoting induction of tissue-specific toxicity and inflammatory responses, immunosuppression, and inhibition of gap junction intercellular communication [2, 3]. Despite these proposals, the molecular mechanisms of non-genotoxic carcinogens remain largely unknown. AID is induced by TNF-a, IL-4, and estrogen in some types of cancer cells and epithelial cells [5, 6]

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