Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2

Abstract

Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a 'good' transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2-small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

“…2 Indeed, while, on the one hand, NRF2 can protect normal cells from oxidative stress and DNA-damaging electrophiles, on the other hand, it can confer cytoprotection against high endogenous levels of reactive oxygen species, thus increasing survival and resistance to chemotherapy of cancer cells. 27 The results stemming from our in vivo and in vitro studies prove that Nrf2 plays a tumorigenic role and that inhibition of Nrf2 is sufficient to impair colony-forming ability and in vivo growth of hepatocarcinoma cells. The finding that activating mutations of Nrf2 occur at very early stages of the carcinogenic process suggests that activation of the Nrf2/Keap1 pathway is mandatory for HCC progression and that its inhibition deeply affects the tumorigenic capacity of HCC cells.…”

“…1A,B). Twenty-four of 25 Nrf2 mutations were located in the Nrf2 regions coding for either the LxxQDxDLG motif (spanning amino acids [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] or the DxETGE motif (amino acids 77-82) (Fig. 1C).…”

“…3 Notably, an oncogenic role of NRF2 activation has recently been proposed, based on the finding that its overexpression and/or mutation takes place in many human cancers, including HCC, 5,24,25 and that cancers with high NRF2 levels are associated with poor prognosis. 26,27 However, as pointed out by Sporn and Liby, whether NRF2 plays a pro-or an antitumorigenic role in premalignant lesions or early malignancy is still unclear. 2 Indeed, while, on the one hand, NRF2 can protect normal cells from oxidative stress and DNA-damaging electrophiles, on the other hand, it can confer cytoprotection against high endogenous levels of reactive oxygen species, thus increasing survival and resistance to chemotherapy of cancer cells.…”

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

“…Enhanced Nrf2-driven gene expression has been suggested not only to protect cells from oxidative stress and contribute to chemoprevention but also to cause resistance to chemotherapy and promote cancer cell growth (Wang et al, 2008;Zhang, 2010). Because of these potential negative roles of Nrf2 signaling in chemotherapy, suppression of Nrf2/ARE activity during cancer treatment could be clinically beneficial (Kensler and Wakabayashi, 2010).…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…132 Although Nrf2 activation may be protective against cancer development in early stages, 133 sustained or hyperactivation activation of Nrf2 with increased expression of cytoprotective genes enhanced cancer cell survival and conferred resistance to chemotherapy. 133 Targeted deletion of Nrf2 reduced urethaneinduced tumorigenesis in lungs of mice by minimizing the expression of ARE-responsive genes.…”