OncoTarget 2013-Jan Link
Abstract
The transcription factor nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, is a master regulator of the anti-oxidative stress response and positively controls the expression of a battery of anti-oxidative stress response proteins and enzymes implicated in detoxification and glutathione generation. Although its detoxifying activity is important in cancer prevention, it has recently been shown that cancer cells also exploit its protective functions to thrive and resist chemotherapy. NRF2 was also shown to the pentose phosphate pathway and glutaminolysis, which promotes purine synthesis for supporting rapid proliferation and glutathione for providing anti-oxidative stress protection. Evidence obtained from cancer patients and cell lines suggest that NRF2 is highly active in a variety of human cancers and is associated with aggressiveness. p53 is a tumor suppressor that also promotes an anti-oxidative stress metabolic program and glutaminolysis. Here we will discuss the similarities between NRF2 and p53 and review evidence that p53 might be exploited by cancer cells to gain protection against oxidative stress, as is the case for NRF2. We discuss findings of co-regulation between these transcription factors and propose possible therapeutic strategies that can be used for treatment of cancers that harbor WT p53 and express high levels of NRF2.
Figure 1: NRF2 and p53 regulate the expression of proteins involved in protection ageist oxidative stress. NRF2 and p53 target genes (red and blue) that are contributing to protection against oxidative stress directly or by promoting glutathione synthesis by facilitating glutaminolysis, through direct synthesis or by facilitating NADPH production. NRF2, nuclear factor (erythroid-derived 2)-like 2; HMOX1, Heme Oxygenase 1; GCL, γ-glutamylcysteine ligase; GPX, glutathione peroxidase; NQO1, NAD(P)H quinine dehydrogenase; SENS, sestrins; GLS 1/2, glutaminase 1/2; GLH, reduced glutathione; NAPDH, Nicotinamide adenine dinucleotide phosphate.
Figure 2: Positive and negative (up or down) co-regulation between p53 and NRF2. Top to bottom. KEAP1 interacts with NRF2 and forms a complex with the E3 ligase CUL3 that results in NRF2 ubiquitylation and degradation by the proteasome (depicted as a blue X). The p53 target gene, p21, interacts with KEAP1 and inhibits NRF2 ubiquitylation and degradation. p53 is degraded by the proteasome in a ubiquitin n dependent manner. The NFR2 target, NQO1, interacts with p53 and protects it from degradation. NRF2 target gene, MDM2, promotes p53 ubiquitylation and degradation by the proteasome. P53 is a transcriptional repressor of NRF2. NRF2, nuclear factor (erythroid-derived 2)-like 2NQO1, NAD(P)H quinine dehydrogenase; mdm2, mouse double minute 2.
Targeting anti-oxidative stress proteins as possible anti-cancer therapy
Stabilization or reactivation of p53 throughout the use of small molecules is a promising therapeutic strategy [96, 98, 153–157]. However, we believe that alternative approaches should be explored in order to win the war against cancer [158–163].
In light of the model that NRF2 and p53 synergize in enhancing the cellular anti-oxidative stress mechanisms, we reason that cancer cells that exhibit high NRF2 levels and harbor WT p53 will be more dependent on these pathways to sustain chemo resistance. It is therefore tempting to speculate that targeting the anti-oxidative stress modules, that are promoted by NRF2 and p53, in combination with chemotherapeutic that will increase ROS, such as Doxorubicin [164], is a rational approach for treating such cases. Some of potential drugable targets would be the glutaminolysis pathway, the glutathione generating pathway, anti-oxidative stress proteins and NRF2. As discussed above, p53 and NRF2 promote glutaminolysis that supplies the glutamate and NADPH to generate glutathione to battle oxidative stress (Fig. 1). Targeting Kidney type Glutaminase (KGA), an essential enzyme in glutaminolysis, using an inhibitor such as BPTES, could inhibit glutaminolysis [165–167]. Indeed, this compound was shown to inhibit growth of MYC transformed P493 cells in vivo by increasing ROS and reducing glutathione levels in these cells [166]. Another strategy to reduce glutathione is by targeting γ-glutaminase, a rate limiting enzyme in the generation of glutathione, using BSO, a compound that has been shown to be well tolerated in man [168].
Piperlongumine has been shown to be selectively toxic to cancer cells and its mechanism of action was proposed to involve enhancing ROS in cancer cells by binding to a wide number of anti-oxidative stress proteins [169]. It is therefore plausible that piperlongumine could be useful in treating cancers that rely on anti-oxidative stress proteins that are induced by NRF2 and p53. Using 80 piperlongumine analogs it was recently demonstrated that the toxic effect of piperlongumine is due to its activity in crosslinking glutathione to proteins and depletion of cellular glutathione [170].
A more direct approach could be the targeting of NRF2 itself using brusatol, a natural compound that was shown to inhibit NRF2 by promoting its degradation [171]. The same study showed that brusatol synergized with chemotherapeutic agents in vitro and in xenograft models and to induce death in tumors that have acquired drug resistance through NRF2.
It is now clear that the cancer cells will utilize endogenous protective mechanisms to evolve chemoresistance [172–174]. It is therefore important that we take a close look at what we believe are tumor suppressor proteins and pathways as they might paradoxically be hijacked by cancer cells to promote their growth and survival. NRF2 and p53 may well be the two-faced Januses of cancer.