The PTEN/NRF2 Axis Promotes Human Carcinogenesis

Abstract

Aims: A recent study conducted in mice reported that liver-specific knockout of tumor suppressor Pten augments nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional activity. Here, we further investigated how phosphatase and tensin homolog deleted on chromosome 10 (PTEN) controls NRF2 and the relevance of this pathway in human carcin ogenesis. Results: Drug and genetic targeting to PTEN and phosphoproteomics approaches indicated that PTEN leads to glycogen synthase kinase-3 (GSK-3)-mediated phosphorylation of NRF2 at residues Ser 335 and Ser 338 and subsequent beta-transducin repeat containing protein (b-TrCP)-dependent but Kelch-like ECH-associated protein 1 (KEAP1)-independent degradation. Rescue experiments in PTEN-deficient cells and xerographs in athymic mice indicated that loss of PTEN leads to increased NRF2 signature which provides a proliferating and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1). Innovation: These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3/b-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas. Conclusion: Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target. Antioxid. Redox Signal. 21, 2498-2514.

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

“…We clearly showed that metformin upregulated the Nrf2 system, while LPS treatment downregulated the Nrf2 system in both HFD-fed mice and HepG2 cells ( Figure 3C and 3D, Supplementary Figure 2 and 3). These results are in line with previous reports showing the interactions of the effects of metformin and LPS on the Nrf2 system [34,35] . The underlying regulatory mechanisms of LPS on the Nrf2 system were not addressed in the current study.…”

“…The reciprocal regulation between Nrf2 system function and PTEN expression has been suggested by several studies [34,40] . In this study, by using an Nrf2 inhibitor, we found that Nrf2 is causally involved in the effect of metformin on the regulation of PTEN and insulin signaling (Supplementary Figure 3).…”

“…Because LPS is reported to promote proteasome-degrading function [37] , Nrf2 turnover may be accelerated by LPS. There is also a report showing that PTEN promotes Nrf2 phosphorylation-dependent degradation [34] , and therefore, LPS could promote Nrf2 degradation by upregulating PTEN expression. Interestingly, metformin has been shown to inhibit LPS-evoked inflammatory signaling through regulating ATF-3 [38,39] and has been recently found to activate Nrf2 to inhibit the inflammation response [35] .…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…One of these phosphatases is PTEN (Lee et al, 2002;Kitagishi and Matsuda, 2013;Han et al, 2015). The catalytic C124 residue of PTEN can be modified through adduct formation with strong electrophiles such as CDDO-Im (Pitha-Rowe et al, 2009) and tertbutylhydroquinone (Rojo et al, 2014b). Then, the increased activation of the PI3K/AKT pathway involves inhibition of GSK-3 and subsequent stabilization of NRF2 (Fig.…”

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

“…I/R-induced Nrf2 activation directly upregulates estrogen sulfotransferase and in turn increases estrogen breakdown, limiting Nrf2 activity and gender-dependently affecting I/R injury (Guo et al, 2015). In addition, the crosstalk of Nrf2 signaling with the PTEN-GSK-3-b-TrCP pathway and the p62-mediated autophagy pathway has been demonstrated (Komatsu et al, 2010;Ni et al, 2014;Rojo et al, 2014;Taguchi et al, 2014). Han et al (2014) uncovered an ERa/liver X receptor (LXR)/ sterol regulatory element-binding protein (SREBP) 1 pathway modulating hepatic lipid metabolism (Han et al, 2014).…”