Review ArticleOncogenic potential of Nrf2 and its principal target protein heme oxygenase-1☆
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Section snippets
Role of Nrf2 in the maintenance of redox balance in normal cells
Oxidative stress is the pathogenic outcome resulting from an imbalance between production of reactive oxygen species (ROS) and the cellular antioxidant capacity. Intracellular accumulation of relatively high concentrations of ROS induces oxidative damage in DNA, which may cause initiation of cancer. Moreover, oxidative stress can stimulate the clonal expansion of mutated cells and hence can promote tumorigenesis as well by stimulating redox-responsive growth signaling [1].
Nrf2 is the
Mechanisms underlying constitutive activation of Nrf2 in cancer cells
Under physiological conditions, Nrf2 is sequestered in the cytoplasm as an inactive complex with its repressor Keap1 anchored to actin. Keap1 is a member of a large family of proteins containing an N-terminal region, the Broad complex/Tramtrack/Bric-a-brac (BTB) domain, an intervening region (IVR), a Kelch repeat or double-glycine repeat (DGR), and a C-terminal region (CTR) [9]. Nrf2 possesses six highly conserved domains termed Nrf2–ECH homology (Neh) domains [10]. Of these Neh domains, Neh1,
Proliferation of cancer (stem) cells
As a highly reducing environment has been shown to stimulate cell proliferation [38], the reduced redox tumor microenvironment arising from persistent activation of Nrf2 could favor the doubling of stem-cell-like populations, promoting the initial event of tumor formation. In support of this speculation, lower ROS levels have been found in many cancer stem cells compared to their nontumorigenic counterparts, allowing them to maintain a high proliferative capacity while preventing
v-ErbB2 erythroblastic leukemia viral oncogene homolog 2 (ErbB2)
ErbBs are receptor tyrosine kinases essential for cell proliferation and differentiation. Overexpression of ErbB2 is often observed in several human tumors and is correlated with poor prognosis [63], [64]. ErbB2 activates phosphoinositide 3-kinase (PI3K)–protein kinase B/Akt signaling, and overexpression of ErbB2 reduces expression of cell cycle inhibitors (e.g., p21 and p27) and apoptosis-related components [65]. Nrf2 may regulate ErbB2–PI3K/Akt signaling. Thus, stable inhibition of Nrf2
HO-1 as a potential player in Nrf2-mediated cancer cell survival and resistance to anticancer therapy
HO-1 is a member of the heat shock protein family, and its expression is mainly upregulated by Nrf2. The promoter region of human HO-1 harbors the AREs for Nrf2 binding. It is the rate-limiting enzyme in the degradation of heme into biliverdin, carbon monoxide (CO), and free iron. HO-1 plays a pivotal role in the maintenance of cellular redox homeostasis and hence prevents transformation of normal cells to precancerous or malignant ones by counteracting ROS-mediated carcinogenesis [86], [87].
HO-1 and cancer cell resistance to anticancer therapy
HO-1 expression in tumor cells can be further increased by anticancer treatments, such as chemotherapy, radiotherapy, and photodynamic therapy. Pharmacological inhibitors of HO-1 have been shown to exert anticarcinogenic effects and sensitize cancer cells to anticancer therapy [93], [94], suggesting that HO-1 and its products may be involved in the development of a resistant phenotype as well as manifestation of malignancy. Therefore, targeting HO-1 can be considered an important strategy in
HO-1 in metastasis and angiogenesis
HO-1 overexpression in cancer patients with non-small-cell lung carcinoma has been associated with a poorer prognosis and a higher metastatic state [91]. The invasive and migratory abilities of human lung adenocarcinoma cells increased after exogenous HO-1 overexpression and decreased after siRNA-mediated silencing of HO-1 expression [91]. HO-1 influences the expression of metastasis-associated proteins matrix metalloproteinase (MMP)-9, EGFR, and CD147 [91]. The expression of MMP9 and VEGF-A
HO-1 polymorphism and cancer risk
A HO-1 gene promoter polymorphism was reported to be associated with the risk of several human malignancies. (GT)n dinucleotide repeats present in the 5′ flanking region of the HO-1 gene promoter are polymorphic, which influences the transcriptional activity of the gene. The short (GT)n dinucleotide repeats are linked to an increased HO-1 upregulation. For instance, the constitutive expression of HO-1 protein was associated with a shorter (GT)n repeat in human bladder cancer patients under ALA
Concluding remarks
High levels of oxidative stress exhibit cytotoxicity, inhibiting cell proliferation and leading to apoptotic/necrotic cell death, whereas low or intermediate levels of oxystress are effective at DNA damage, causing mutation and promoting proliferation of cells, and ultimately inducing carcinogenesis via initiation, promotion, and progression [137].
Nrf2 plays a key role in cellular adaptive survival responses to a wide spectrum of environmental insults, including oxidative stress. This
Acknowledgments
This work was supported by a Global Core Research Center grant (2011–0030676 to Y.-J. Surh) and a Basic Science Research Program grant (NRF 2009–0077736 to H.-K. Na) from the National Research Foundation. The authors acknowledge editorial support from Dr. Do-Hee Kim in reference citations and preparing the illustrations.
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This article was intended for publication in FRBM Special Issue: Antioxidants; 66C 2014, http://www.sciencedirect.com/science/journal/08915849/66