Dietary Phytochemicals Targeting Nrf2 to Enhance the Radiosensitivity of Cancer

Abstract

Nowadays, cancer has become the second leading cause of death worldwide. Radiotherapy (RT) is the mainstay in management of carcinoma; however, overcoming radioresistance remains a great challenge to successfully treat cancer. Nrf2 is a key transcription factor that is responsible for maintaining cellular redox homeostasis. Activation of Nrf2 signaling pathway could upregulate multifarious antioxidant and detoxifying enzymes, further scavenging excessive reactive oxygen species (ROS). Despite its cytoprotective roles in normal cells, it could also alleviate oxidative stress and DNA damage caused by RT in cancer cells, thus promoting cancer cell survival. Accumulating evidence indicates that overactivation of Nrf2 is associated with radioresistance; therefore, targeting Nrf2 is a promising strategy to enhance radiosensitivity. Dietary phytochemicals coming from natural products are characterized by low cost, low toxicity, and general availability. Numerous phytochemicals are reported to regulate Nrf2 and intensify the killing capability of RT through diverse mechanisms, including promoting oxidative stress, proapoptosis, and proautophagy as well as inhibiting Nrf2-mediated cytoprotective genes expression. This review summarizes recent advances in radiosensitizing effects of dietary phytochemicals by targeting Nrf2 and discusses the underlying mechanisms, including N6-methyladenosine (m6A) modification of Nrf2 mediated by phytochemicals in cancer.

Figure 1

Domain structure of Nrf2 protein.

Figure 2

Domain structure of Keap1 protein.

Figure 3

Schematic representation of the Keap1-Nrf2-ARE pathway. Under basal condition, the DLG and ETGE motifs of Nrf2 interact with the BTB domain contained within Keap1, which brings Nrf2 to the Cul3-based ubiquitin E3 ligase and targets the 26S proteasome for degradation in cytoplasm. Under stressed condition, the modified cysteine residues disturb the binding between Keap1 and Cul3, which protect Nrf2 from proteasomal degradation. The accumulated Nrf2 subsequently translocates into the nucleus, dimerizes with sMaf, and binds to the ARE which is located in the promoter of the target cytoprotective genes, ultimately driving their robust expression.

Figure 4

The signaling pathways involved in Nrf2-mediated radioresistance and the potential targets of dietary phytochemicals. Radiation produces abundant ROS, leading to the activation of signaling pathways including Nrf2, p38 MAPK, and Akt/PI3K. Upregulation of Nrf2 would further elevate the levels of antioxidants, such as HO-1, NQO1, Trx1, GPx, and GSH in cancer cells, ultimately leading to tumor radioresistance. Nrf2 has also been implicated in the roles of other genes in cancer radioresistance via interactions with NF-κB, HIF-1α, ATM, ATR, and p21^Cip1/WAF1. Among these dietary phytochemicals, EGCG is capable to enhance the killing effects of RT by promoting Nrf2 expression; however, other phytochemicals, such as BBR, BRU, CGN, AIF, ISL, DADS, FA, genistein, and cordycepin, have been shown to enhance radiosensitivity through inhibiting Nrf2 expression, or suppressing Nrf2 nuclear translocation, Akt/PI3K/NF-κB pathway, and p38 MAPK/NF-κB pathway, or promoting Keap1 expression.

Figure 5

Chemical structures of dietary phytochemical targeting Nrf2 that could potentially enhance radiosensitivity.

Figure 6

Potential mechanisms underlying m6A modification of Nrf2 mRNA and targets of dietary phytochemicals. The m6A RNA methylation of Nrf2 is conducted by methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). “Writers” like METTL3/14 could catalyze m6A modification on Nrf2 mRNA. “Erasers,” including FTO and ALKBH5, could remove m6A bases. “Readers,” such as YTHDF1-3 and YTHDC2, could recognize the sites modified by m6A to mediate diverse functions such as translation and RNA degradation. In addition, the expression of Nrf2 is regulated via m6A methylation, which is accomplished by modulation of “erasers” or “readers” by the dietary phytochemical compounds, EGCG and genistein.