Abstract
Although multidrug-resistance-associated protein-1 (MRP1) is a major contributor to multi-drug resistance (MDR), the regulatory mechanism of Mrp1 still remains unclear. Nrf2 is a transcription factor that regulates cellular defense response through antioxidant response elements (AREs) in normal tissues. Recently, Nrf2 has emerged as an important contributor to chemo-resistance in tumor tissues. In the present study, the role of Nrf2-ARE pathway on regulation of Mrp1 was investigated. Compared with H69 lung cancer cells, H69AR cells with MDR showed significantly higher Nrf2-ARE pathway activity and expression of Mrp1 as well. When Nrf2 was knocked down in H69AR cells, MRP1's expression decreased accordingly. Moreover, those H69AR cells with reduced Nrf2 level restored sensitivity to chemo-drugs. To explore how Nrf2-ARE pathway regulates Mrp1, the promoter of Mrp1 gene was searched, and two putative AREs—ARE1 and ARE2—were found. Using reporter gene and ChIP assay, both ARE1 and ARE2 showed response to and interaction with Nrf2. In 40 cases of cancer tissues, the expression of Nrf2 and MRP1 was measured by immunohistochemistry (IHC). As the quantitive data of IHC indicated, both Nrf2 and MRP1 showed significantly higher expression in tumor tissue than adjacent non-tumor tissue. And more important, the correlation analysis of the two genes proved that their expression was correlative. Taken together, theses data suggested that Nrf2-ARE pathway is required for the regulatory expression of Mrp1 and implicated Nrf2 as a new therapeutic target for MDR.
Highlights
Multidrug resistance (MDR) is a major obstacle in the treatment of malignant carcinoma
The activation of Nrf2 pathway was compared between H69 and H69AR cells
The recent emerging reports demonstrated that Nrf2-antioxidant response elements (AREs) pathway is responsible for phase II enzymes, and Multidrug-resistance-associated proteints (MRPs), for instance, there is AREs found in the promoter region of MRP2 gene [15]
Summary
Multidrug resistance (MDR) is a major obstacle in the treatment of malignant carcinoma. It is a phenomenon in which cancer cells exhibit reduced sensitivity to a large group of unrelated drugs with different mechanisms of pharmacological activity whether it occurs in primary therapy (intrinsic) or is acquired during or after treatment [1]. The resistance phenomena may be explained by a number of aspects, which include reduced drug accumulation due to the over-expression of transport proteins, increased detoxification, altered targets and impaired apoptosis pathway [2]. As one of the drug transporting ABCC proteins, MRP1 was first cloned highly over-expressed in a doxorubicin-selected multidrug resistant human lung carcinoma cell line H69AR [4]. The 190 kDa MRP1 can confer resistance to doxorubicin, and many other widely used antineoplastic drug, such as methotrexate (MTX), daunorubicin, vincristine and etoposide [5]
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