Abstract
BackgroundThe transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious.MethodsWe employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided.ResultsWe found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1α destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers.ConclusionsOur data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth.
Highlights
The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer
Overall our results indicate that defects in the cellular antioxidant capacity contribute to reactive oxygen species (ROS) accumulation during transformation, and that oncogene-induced Nrf2 repression is an adaptive response for certain cancer cells to acquire a pro-oxidant state that favors cell survival and tumor growth
In vitro transformation of human mesenchymal stem cell (MSC) leads to an increase in intracellular ROS that contributes to the transformed phenotype To investigate changes in ROS levels during tumorigenesis, we employed a previously developed stepwise transformation model of human MSC (Figure 1A) [31]
Summary
The transcription factor Nrf is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. Activation of the Nrf2-ARE pathway has been proposed as a potential strategy to prevent cancer because of its ability to suppress genotoxic insults by inducing antioxidants and detoxifying enzymes [14,15,16]. In this regard, nrf2-/- mice are more susceptible to chemically-induced cancer [17,18,19,20], and Nrf2-deficiency has been suggested to favor metastasis [21].
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