Abstract
Overexpression of ABCB1, ABCC1 and ABCG2 in tumor tissues is considered a major cause of limited efficacy of anticancer drugs. Gene expression of ABC transporters is regulated by multiple mechanisms, including changes in the DNA methylation status. Most of the studies published so far only report promoter methylation levels for either ABCB1 or ABCG2, and data on the methylation status for ABCC1 are scarce. Thus, we determined the promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in 19 human cancer cell lines. In order to contribute to the elucidation of the role of DNA methylation changes in acquisition of a multidrug resistant (MDR) phenotype, we also analyzed the promoter methylation patterns in drug-resistant sublines of the cancer cell lines GLC-4, SW1573, KB-3-1 and HL-60. In addition, we investigated if aberrant promoter methylation levels of ABCB1, ABCC1 and ABCG2 occur in tumor and tumor-surrounding tissues from breast cancer patients.Our data indicates that hypomethylation of the ABCC1 promoter is not cancer type-specific but occurs in cancer cell lines of different origins. Promoter methylation was found to be an important mechanism in gene regulation of ABCB1 in parental cancer cell lines and their drug-resistant sublines. Overexpression of ABCC1 in MDR cell models turned out to be mediated by gene amplification, not by changes in the promoter methylation status of ABCC1. In contrast to the promoters of ABCC1 and ABCG2, the promoter of ABCB1 was significantly higher methylated in tumor tissues than in tumor-adjacent and tumor-distant tissues from breast cancer patients.
Highlights
Chemotherapy, surgery and radiation therapy are todays main pillars of cancer treatment
We were interested in the DNA methylation status of the main promoters known to regulate most of the transcriptional activity but not in that of alternative promoters linked to tissue-specific gene expression [20, 46]
A significant difference was found in the DNA methylation status of these CpGs between parental SW480 cells and SW480/ tria, a triapine-resistant subline overexpressing ABCB1 [47]
Summary
Chemotherapy, surgery and radiation therapy are todays main pillars of cancer treatment. The efficacy of chemotherapy is, limited due to drug resistance. For some types of cancer, e.g. cancers derived from colon, kidney, adrenal gland, liver and pancreas, resistance often exists even before chemotherapy started (intrinsic resistance). E.g. breast and small cell lung cancer, frequently develop resistance after an initial positive response (acquired resistance) [1]. Multidrug resistance (MDR), the simultaneous resistance to a broad range of structurally unrelated drugs with different modes of action, is a particular challenge in cancer treatment [2]. Chemotherapy resistance can be caused by mechanisms in the cancer cells and/or by characteristics of the tumor microenvironment [3]. Processes that limit drug uptake or increase drug inactivation, drug efflux or the repair of DNA lesions caused by cancer treatment reduce the efficacy of chemotherapy [6]
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