Elsevier

European Journal of Cancer

Volume 41, Issue 16, November 2005, Pages 2577-2586
European Journal of Cancer

Transcription factors and drug resistance

https://doi.org/10.1016/j.ejca.2005.08.007Get rights and content

Abstract

Intrinsic or acquired resistance to anticancer agents is a major obstacle to the success of chemotherapy. Anticancer agents are known to modulate signal transduction pathways and alter expression of genes that play an important role in drug resistance. Emerging evidence suggests that the complexity of genomic response against anticancer agents arise from elaborate gene expression by multiple transcription factors. Here, we briefly describe the development of solid tumours and the appearance of drug-resistant cells. We also review what is known of the transcription factors that are involved in resistance to drugs, particularly cisplatin.

Introduction

The transcriptional regulation of gene expression requires the participation of a large and diverse collection of nuclear factors, such as sequence-specific DNA-binding proteins, transcriptional cofactors, chromatin-remodelling factors, modifying enzymes and basal transcription factors 1, 2, 3. These factors interact in a complex fashion.

Cancer is a genomic disease that is thought to arise from the accumulation of mutations leading to immortal cell proliferation. Either the activation of protooncogenes or the inactivation of tumour suppressor genes is responsible for this activity. Many protooncogenes and tumour-suppressor genes encode transcription-related factors and modulate cellular sensitivity to anticancer agents. However, little is known about those that affect responses to anticancer agents. Both intrinsic and acquired drug-resistance hinder the treatment of solid tumours. Anticancer agents activate a variety of signal transduction pathways and trigger genome-wide responses. Transcription factors contribute to drug-induced responses and can induce either transient or acquired drug resistance. Molecular dissection of the functions of transcription factors allows the complexities of solid tumour development and drug resistance to be elucidated.

Our research has focused on factors affecting the sensitivity of solid tumours to anticancer agents. The post-genomic approach has enabled us to analyse the complexity of genetic responses to anticancer agents. This is likely to reflect the activity of transcriptional networks that control the expression of many different genes and depend on the combinatorial action of numerous transcription-related factors. Investigation of the interactions between factors that are activated in response to anticancer agents is therefore essential for understanding the complexity of the genomic response. Moreover, these factors and molecular interactions constitute potential targets for chemotherapy. It is well-known that drug resistance is influenced by many factors, which affect intracellular drug accumulation, levels of cellular thiols and DNA-repair activity. The importance of a particular mechanism varies with the tissue origin of a tumour and the anticancer agents that are used. In this review, we focus mainly on selected transcription factors that are involved in the development of solid tumours and cisplatin resistance.

Section snippets

Solid tumour development and transcription factors

Alterations affecting transcription factors that are encoded by protooncogenes and tumour-suppressor genes are crucially involved in the malignant transformation of epithelial cells 4, 5. The common biochemical phenotype of rapidly growing cells is their ability to utilise glucose at high rates [6]. Tumour cells grow under hypoxic conditions and produce acid metabolites, such as lactate; hence, they activate transcription factors, such as hypoxia-inducible factor-1 (HIF-1), nuclear factor-κB

Intrinsic and acquired resistance

The development of drug resistance by tumour cells is a major obstacle to cancer chemotherapy [18]. There are two mechanisms for the appearance of drug-resistant cells during cancer chemotherapy (Fig. 2). The first is selection, which implies that drug-insensitive cells exist in cancer cell populations and can survive selectively during chemotherapy. Such drug-resistant cells might be generated as a result of genetic instability. The tissue-specific expression of drug-resistance-related genes

Drug resistance and transcription factors

Drug and apoptosis resistance are two sides of the same coin. Oncogenic transcription factors, such as Myc, NF-κB, AP-1 and tumour suppressor gene products such as p53 and p73 have been connected to several aspects of carcinogenesis, including the cell cycle, differentiation, apoptosis and drug resistance 4, 45. c-Myc binds to E-box and transactivates various genes including YB-1 [46]. Low expression of c-Myc results in increased susceptibility to cisplatin 47, 48. NF-κB is well-known as key

Conclusions

Knowledge of the molecular links between transcription factors and drug resistance promises to provide the foundation for novel molecularly targeted cancer chemotherapies. Microarray studies of drug-treated cells or drug-resistant cell lines have mainly identified easily detected and highly expressed genes. These studies might fail to reveal the transcriptional network that governs the genomic response to anticancer agents, because transcription factors might function mainly by interacting with

Conflict of interest statement

This work was supported in part by Mext.Kakenhi (13218132), an AstraZeneca Research Grant 2002, a grant-in-aid for cancer research from the Fukuoka Cancer Society.

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