Transcription factors and drug resistance
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.
References (91)
- et al.
Cooperation between complexes that regulate chromatin structure and transcription
Cell
(2002) - et al.
Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects
Cell
(2002) - et al.
The hallmarks of cancer
Cell
(2000) - et al.
New anticancer strategies targeting HIF-1
Biochem Pharmacol
(2004) - et al.
Role of Jun and Jun kinase in resistance of cancer cells to therapy
Drug Resist Updat
(2003) - et al.
Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy
Cancer Treat Rev
(2003) - et al.
Structural and functional characterization of two human V-ATPase subunit gene promoters
Biochim Biophys Acta
(2003) - et al.
Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents
J Biol Chem
(2002) - et al.
DNA topoisomerase II poison TAS-103 transactivates GC-box-dependent transcription via acetylation of Sp1
J Biol Chem
(2005) Transcription factors and cancer: an overview
Toxicology
(2002)
The (patho)physiological functions of the MRP family
Drug Resist Updat
Cisplatin and DNA repair in cancer chemotherapy
Trends Biochem Sci
Nuclear translocation of the Y-box binding protein by ultraviolet irradiation
FEBS Lett
The direct activation of human multidrug resistance gene (MDR1) by anticancer agents
Biochem Biophys Res Commun
Direct involvement of the Y-box binding protein YB-1 in genotoxic stress-induced activation of the human multidrug resistance 1 gene
J Biol Chem
p73 Interacts with c-Myc to regulate Y-box-binding protein-1 expression
J Biol Chem
Glutathione depletion induced by c-Myc downregulation triggers apoptosis on treatment with alkylating agents
Neoplasia
Inhibition of NF-κB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models
J Biol Chem
Expression of glutathione S-transferase P1-1 in leukemic cells is regulated by inducible AP-1 binding
Cancer Lett
Apoptosis: a link between cancer genetics and chemotherapy
Cell
The rise of DNA methylation and the importance of chromatin on multidrug resistance in cancer
Exp Cell Res
Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling
J Biol Chem
The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair
J Biol Chem
Co-expression of Y box-binding protein-1 and P-glycoprotein as a prognostic marker for survival in epithelial ovarian cancer
Gynecol Oncol
Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human breast carcinoma
Cancer Lett
Lack of c-Jun activity increases survival to cisplatin
FEBS Lett
Transcription regulation and animal diversity
Nature
Cancer genes and the pathways they control
Nat Med
Why do cancers have high aerobic glycolysis?
Nat Rev Cancer
Targeting HIF-1 for cancer therapy
Nat Rev Cancer
Nuclear transcription factor-κB as a target for cancer drug development
Leukemia
Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks
Oncogene
Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells
Cancer Res
Low pH enhances Sp1 DNA binding activity and interaction with TBP
Nucleic Acids Res
Introduction to resistance to anticancer agents
Oncogene
Transcription factors and neoplasia: vistas in novel drug design
Clin Cancer Res
Tumour stem cells and drug resistance
Nat Rev Cancer
Transcriptional regulation of ABC drug transporters
Oncogene
Glutathione-associated enzymes in anticancer drug resistance
Cancer Res
The role of glutathione-S-transferase in anti-cancer drug resistance
Oncogene
DNA repair: enzymatic mechanisms and relevance to drug response
J Natl Cancer Inst
Biochemical, cellular, and pharmacological aspects of the multidrug transporter
Annu Rev Pharmacol Toxicol
Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C, and ultraviolet light
Cancer Res
Enhanced expression of the human multidrug resistance 1 gene in response to UV light irradiation
Cell Growth Differ
Targeted disruption of one allele of the Y-box binding protein-1 (YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin and mitomycin C
Cancer Sci
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2017, Cancer LettersCitation Excerpt :Further elucidation of the association between cisplatin-resistance and the EMT may enable development of novel therapeutic approaches for chemoresistant tumors. Multiple mechanisms lead to cisplatin resistance [17–20], including increased extrusion of cytotoxic agents by energy-dependent pumps such as the ATP-binding cassette (ABC) transporters. The ABC transporters MRP1 (Multidrug Resistance Associated Protein 1) and ABCG2 (breast cancer resistance protein, BCRP) contribute to multidrug resistant phenotypes in several types of advanced cancer [60–63], including NPC [64].