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Review
. 2024 Aug 25;14(8):3935-3961.
doi: 10.62347/LZVO6743. eCollection 2024.

Nrf2 in human cancers: biological significance and therapeutic potential

Yu Tian  1   2 , Lixin Tang  3 , Xin Wang  4 , Yanqin Ji  5 , Yanyang Tu  1
Affiliations
Review

Nrf2 in human cancers: biological significance and therapeutic potential

Yu Tian et al. Am J Cancer Res. .

Abstract

The nuclear factor-erythroid 2-related factor 2 (Nrf2) is able to control the redox balance in the cells responding to oxidative damage and other stress signals. The Nrf2 upregulation can elevate the levels of antioxidant enzymes to support against damage and death. In spite of protective function of Nrf2 in the physiological conditions, the stimulation of Nrf2 in the cancer has been in favour of tumorigenesis. Since the dysregulation of molecular pathways and mutations/deletions are common in tumors, Nrf2 can be a promising therapeutic target. The Nrf2 overexpression can prevent cell death in tumor and by increasing the survival rate of cancer cells, ensures the carcinogenesis. Moreover, the induction of Nrf2 can promote the invasion and metastasis of tumor cells. The Nrf2 upregulation stimulates EMT to increase cancer metastasis. Furthermore, regarding the protective function of Nrf2, its stimulation triggers chemoresistance. The natural products can regulate Nrf2 in the cancer therapy and reverse drug resistance. Moreover, nanostructures can specifically target Nrf2 signaling in cancer therapy. The current review discusses the potential function of Nrf2 in the proliferation, metastasis and drug resistance. Then, the capacity of natural products and nanostructures for suppressing Nrf2-mediated cancer progression is discussed.

Keywords: Cancer; Nrf2; cancer drug resistance; cell death; proliferation and metastasis.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
An overview of Nrf2 signaling. Nrf2 is a regulator of redox balance and when there is oxidative damage, the stimulation of Nrf2 occurs. This prevents the proteasomal degradation of Nrf2 and therefore, its upregulation can enhance its nuclear transfer to induce antioxidant defense system.
Figure 2
Figure 2
Association of Nrf2 with the proliferation and metastasis of tumor cells. The upregulation of Nrf2 by UCHL3 can enhance the metastasis of cancer cells. Moreover, nestin impairs Keap1 to upregulate Nrf2 in causing tumorigenesis. The upregulation of Nrf2 by WTAP reduces ferroptosis, while ALKBH5 promotes ferroptosis through Nrf2 downregulation. Moreover, DDRGK1 induces drug resistance through Nrf2 upregulation.
Figure 3
Figure 3
Nrf2 and cell death mechanisms in cancer. The main regulation is related to the apoptosis, autophagy and ferroptosis. About the regulation of autophagy by Nrf2, it should be considered that function of autophagy in cancer is like a double-edged sword and it has ability of impairing/accelerating tumorigenesis and reversing/inducing drug resistance. Moreover, upregulation of autophagy can prevent apoptosis and ferroptosis in tumor cells.
Figure 4
Figure 4
The regulation of Nrf2 by non-coding RNAs in cancer. The miRNAs can change the expression of Nrf2 by binding to 3’-UTR. Moreover, the Nrf2 downregulates miR-144-3p expression to increase cisplatin resistance. miR-101 induces apoptosis through Nrf2 downregulation. Moreover, LINC00239 impairs ferroptosis through upregulation of Nrf2.
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