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Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis.

ABSTRACT: Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system Xc-) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles' heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics.

SUBMITTER: Fan Z

PROVIDER: S-EPMC5608917 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis.

Fan Z Z Wirth A-K AK Chen D D Wruck C J CJ Rauh M M Buchfelder M M Savaskan N N

Oncogenesis 20170814 8

Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and o ...[more]

PMID: 28805788

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Project description:BackgroundGlutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; however, its role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is largely unknown. We aimed to assess the role of GSTZ1 in HCC and to reveal the underlying mechanisms, which may contribute to finding a potential therapeutic strategy against HCC.MethodsWe first analyzed GSTZ1 expression levels in paired human HCC and adjacent normal tissue specimens and the prognostic effect of GSTZ1 on HCC patients. Thereafter, we evaluated the role of GSTZ1 in aerobic glycolysis in HCC cells on the basis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Furthermore, we assessed the effect of GSTZ1 on HCC proliferation, glutathione (GSH) concentration, levels of reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (NRF2) signaling via gain- and loss- of GSTZ1 function in vitro. Moreover, we investigated the effect of GSTZ1 on diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced hepatocarcinogenesis in a mouse model of HCC.ResultsGSTZ1 was downregulated in HCC, thus indicating a poor prognosis. GSTZ1 deficiency significantly promoted hepatoma cell proliferation and aerobic glycolysis in HCC cells. Moreover, loss of GSTZ1 function depleted GSH, increased ROS levels, and enhanced lipid peroxidation, thus activating the NRF2-mediated antioxidant pathway. Furthermore, Gstz1 knockout in mice promoted DEN/CCl4-induced hepatocarcinogenesis via activation of the NRF2 signaling pathway. Furthermore, the antioxidant agent N-acetylcysteine and NRF2 inhibitor brusatol effectively suppressed the growth of Gstz1-knockout HepG2 cells and HCC progression in Gstz1-/- mice.ConclusionsGSTZ1 serves as a tumor suppressor in HCC. GSH depletion caused by GSTZ1 deficiency elevates oxidative stress, thus constitutively activating the NRF2 antioxidant response pathway and accelerating HCC progression. Targeting the NRF2 signaling pathway may be a promising therapeutic approach for this subset of HCC.

Project description:BackgroundCDGSH iron sulfur domain 2 (CISD2) is an iron-sulfur protein with a [2Fe-2S] cluster, which is critical for cell proliferation and iron homeostasis. It has been demonstrated that aberrant expression of CISD2 is associated with the progression of multiple cancers. However, the underlying mechanism of CISD2 in regulating tumorigenesis remains obscure.MethodsBioinformatics strategies were used to investigate the protein interaction network and functional annotation of CISD2. In the functional experiment, cell viability was measured by CCK-8 kit. The levels of cellular reactive oxygen species (ROS), intracellular free iron, lipid peroxides, and lysosomal activity were determined by DCF-DA, RPA, C11-BODIPY, and cathepsin B staining, respectively. The glutathione (GSH) content was determined using a GSH assay kit.ResultsWe showed that knockdown of CISD2 significantly accelerated the Erastin-induced ferroptotic cell death with excess lipid peroxidation, GSH exhaustion, and iron accumulation, while overexpression of CISD2 hindered the sensitivity to Erastin. Further assays via confocal microscopy and western blot exhibited that CISD2 knockdown markedly enhanced the lysosomal activity, and activated ferritinophagy under the exposure of Erastin. Pharmacological inhibition of lysosomal function could inhibit the degradation of ferritin heavy chain (FTH), and attenuate the phenotypes of ferroptosis, such as accelerated iron accumulation and lipid peroxidation. Notably, we found that Erastin-induced compensatory elevation of nuclear factor erythroid 2-related factor 2 (NRF2) could be eliminated in CISD2 depletion cells. Mechanically, CISD2 knockdown promoted the degradation of autophagy adaptor p62 and resulted in an increased binding affinity of Keap1 with NRF2, thus leading to the increased ubiquitination and subsequent degradation of NRF2. Enforced expression of NRF2 reversed the sensitivity of shCISD2 cells to ferroptosis both in vitro and in vivo. Conversely, enforced expression of Keap1 exacerbated the degradation of NRF2, reduced the transcriptional expression of FTH and heme oxygenase 1 (HO-1), increased the oxidative damage, and thus further facilitated ferroptosis.ConclusionTaken together, our current results illustrated two parallel mechanisms involved in the shCISD2-mediated ferroptosis. One was that shCISD2 enhanced the accumulation of free iron via ferritinophagy-dependent ferritin turnover; the other was that CISD2 depletion induced the inhibition of the p62-Keap1-NRF2 pathway, which resulted in oxidative stress and ferroptosis.

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Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis.

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Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis.

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