Redox Modulating NRF2: A Potential Mediator of Cancer Stem Cell Resistance

Abstract

Tumors contain a distinct small subpopulation of cells that possess stem cell-like characteristics. These cells have been called cancer stem cells (CSCs) and are thought to be responsible for anticancer drug resistance and tumor relapse after therapy. Emerging evidence indicates that CSCs share many properties, such as self-renewal and quiescence, with normal stem cells. In particular, CSCs and normal stem cells retain low levels of reactive oxygen species (ROS), which can contribute to stem cell maintenance and resistance to stressful tumor environments. Current literatures demonstrate that the activation of ataxia telangiectasia mutated (ATM) and forkhead box O3 (FoxO3) is associated with the maintenance of low ROS levels in normal stem cells such as hematopoietic stem cells. However, the importance of ROS signaling in CSC biology remains poorly understood. Recent studies demonstrate that nuclear factor-erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidant defense system, is involved in the maintenance of quiescence, survival, and stress resistance of CSCs. Here, we review the recent findings on the roles of NRF2 in maintenance of the redox state and multidrug resistance in CSCs, focusing on how NRF2-mediated ROS modulation influences the growth and resistance of CSCs.

Figure 1

Involvement of ROS in normal stem cell quiescence and self-renewal. In normal stem cells, modulation of ROS levels can determine quiescence and cell fate progression. At low ROS levels, which are maintained by ATM and FoxO signaling, stem cells remain quiescent and self-renewal activity is enhanced. On the other hand, increased ROS levels result in cell cycle progression, cellular senescence, and apoptosis. The PI3K-AKT pathway is known to elevate ROS levels by negative regulation of FoxO.

Figure 2

Implications of NRF2 signaling in cancer. NRF2 coordinates the expression of genes associated with cellular redox regulation, metabolism, and xenobiotic efflux, and thereby its aberrant activation promotes cancer cell survival, proliferation, and anticancer drug resistance. GCLM, glutamate cysteine ligase modifier subunit; GCLC, glutamate cysteine ligase catalytic subunit; NQO1, NAD(P)H:quinone oxidoreductase 1; SODs, superoxide dismutases; G6PDH, glucose-6-phosphate dehydrogenase; PGD, phosphogluconate dehydrogenase; ME1, malic enzyme 1, MDRs, multidrug resistance proteins; MRPs, multidrug resistance-associated proteins; BCRP, breast cancer resistance protein.

Figure 3

Potential roles of NRF2 signaling in CSCs. In CSC-like cell models, NRF2 is activated through multiple molecular mechanisms in a context-dependent manner. The upregulation of competing proteins such as p62 and p21, activation of PERK, or repressed proteasome function were shown to enhance NRF2 activity in these models. Elevated NRF2 levels in CSCs can contribute to the maintenance of low ROS by upregulating multiple antioxidant genes. In addition, NRF2-mediated expression of ABC transporters elicits efflux of anticancer drugs from cancer cells. Overall, activated NRF2 signaling facilitates CSCs survival and stress resistance, and consequently, it can be suggested that CSCs with high NRF2 activity play a crucial role in tumor recurrence and further progression.