Abstract
NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, therefore, the role of Nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated. We used three human lung cancer cell lines with different degrees of Nrf2 activation: Nrf2 was highly activated in A549 cells, slightly activated in NCI-H292 cells, and not activated in LC-AI cells under unstimulated conditions. A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-AI cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA). The cell proliferation was also most prominently inhibited in A549 cells by treatment with Nrf2-siRNA. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. The degree of DNA crosslink and apoptosis after treatment with cisplatin was significantly elevated in A549 cells by Nrf2-siRNA. Knockdown of Nrf2 arrested the cell cycle at G(1) phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-AI cells. These results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs. Thus, Nrf2 might be a potential target to enhance the effect of anticancer drugs.
Highlights
NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells
We showed that the suppression of Nrf2 activity by Nrf2-small interfering RNAs (siRNA) inhibited the cellular proliferation and reduced the resistance to the anticancer drug CDDP in human lung cancer cells
The inhibitory effects of Nrf2-siRNA were observed most prominently in A549 cells, in which Nrf2 was strongly activated, whereas the inhibitory effects were scarcely observed in LC-AI cells, which do not express Nrf2
Summary
NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. Nrf effector genes bearing antioxidant response element include a majority of antioxidant and phase II detoxifying enzymes [11] In addition to these enzymes, recent studies have shown that Nrf transactivates a wide variety of genes, including several ATP-dependent drug efflux pumps [12, 13]. Been reported that Nrf regulates the proliferation of pulmonary epithelial cells via modulating cellular glutathione levels [14] These findings suggest that activation of Nrf in cancer cells provides advantages for the cell proliferation and the survival from the exposure to anticancer drugs
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