Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer

Zhao, Jiangang; Xu, Lin; Meng, Di; Zeng, Liping; Zhuang, Runzhou; Huang, Sha; Lv, Wang; Hu, Jian

doi:10.3389/fonc.2020.578315

Cited by 42 publications

(30 citation statements)

References 76 publications

(86 reference statements)

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“…It is reported that the transcriptional factor Nrf2 regulates the expression of antioxidant genes and plays a vital role in redox homeostasis. Emerging evidence has shown that Nrf2 pathway is frequently dysregulated in lung cancer and overactivation of the pathway is associated with poor prognosis of NSCLC [ 62 , 63 ]. Our results indicated that apatinib inhibited Nrf2 expression in NSCLC in a concentration- and time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Xie

Zhou

Liang

et al. 2021

J Exp Clin Cancer Res

114

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Background Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. Methods MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. Results We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Conclusion Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.

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Section: Discussionmentioning

confidence: 99%

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Xie

Zhou

Liang

et al. 2021

J Exp Clin Cancer Res

114

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Section: Bad Side Of Nrf2 In Nsclc Progressionmentioning

confidence: 99%

“…This "bad side" action of NRF2 in NSCLC involves the regulation of enzymes related to metabolic reprogramming, where dividing cells conduct aerobic glycolysis (Warburg effect), an important process in cancer progression [74,103]. NRF2 can up-regulate pyruvate kinase (PK), a key enzyme in glycolysis [103]. Indeed, NRF2 is able to increase glucose uptake and redirect it to the pentose phosphate pathway (PPP), which is highly connected to the glycolysis route.…”

Section: Bad Side Of Nrf2 In Nsclc Progressionmentioning

confidence: 99%

“…Altered lipid metabolism is another important NRF2-regulated metabolic feature in cancer. NRF2 reduces the expression of several fatty acid synthesis enzymes, such as fatty acid synthase (FASN), stearoyl CoA desaturase 1 (SCD1) and lipases, including in this last enzyme the phospholipase A2 Group VII (PLA2G7) [103].…”

Section: Bad Side Of Nrf2 In Nsclc Progressionmentioning

confidence: 99%

“…In fact, NRF2 has a key role in the protection of lung cancer cells from ferroptosis, a cell death mechanism involving iron-dependent lipid peroxidation [51]. The involvement of NRF2 in this kind of cell death is caused by NRF2 control of the expression of iron pool-related genes, i.e., ferritin heavy chain 1 (FTH1) [103], glutathione peroxidase 4 (GPX4) and genes involved in glutathione and NADPH syntheses [147].…”

Section: Mechanisms Conferring Nrf2 Activationmentioning

confidence: 99%

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Role of NRF2 in Lung Cancer

Sánchez-Ortega

Carrera

Garrido

2021

Cells

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The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action.

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Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS‐mutant human lung cancer cells

Peter

Sarwar

Mostafa

et al. 2023

Molecular Carcinogenesis

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Kirsten rat sarcoma virus (KRAS) oncogene, found in 20%–25% of lung cancer patients, potentially regulates metabolic reprogramming and redox status during tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS‐mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2‐related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS‐mutant human lung cancer. LC‐MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS‐mutant H358 non‐small cell lung cancer cells. Furthermore, l‐methionine (methyl‐13C) isotope tracer was used to explore the effect of belinostat on one‐carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE‐NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2‐C8 cells (containing pARE‐TI‐luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS‐mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α‐ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino‐succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. 13C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2‐regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS‐mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.

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Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer

Cited by 42 publications

References 76 publications

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Role of NRF2 in Lung Cancer

Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS‐mutant human lung cancer cells

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