bims-nurfca 2023-01-15 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023–01–15
seven papers selected by
Caner Geyik, Istinye University

NRF2 in Cancer: Cross-Talk with Oncogenic Pathways and Involvement in Gammaherpesvirus-Driven Carcinogenesis.
Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.
Inhibitors of Keap1-Nrf2 protein-protein interaction reduce estrogen responsive gene expression and oxidative stress in estrogen receptor-positive breast cancer.
Advances and challenges in therapeutic targeting of NRF2.
Nrf2 regulates the expression of NOX1 in TNF-α-induced A549 cells.
Mitochondrial ROS induced by ML385, an Nrf2 inhibitor aggravates the ferroptosis induced by RSL3 in human lung epithelial BEAS-2B cells.
Anti-Anaplastic Thyroid Cancer (ATC) Effects and Mechanisms of PLX3397 (Pexidartinib), a Multi-Targeted Tyrosine Kinase Inhibitor (TKI).

Int J Mol Sci. 2022 Dec 29. pii: 595. [Epub ahead of print]24(1):

NRF2 in Cancer: Cross-Talk with Oncogenic Pathways and Involvement in Gammaherpesvirus-Driven Carcinogenesis.

Mara Cirone, Gabriella D'Orazi.

  Expanding knowledge of the molecular mechanisms at the basis of tumor development, especially the cross-talk between oncogenic pathways, will possibly lead to better tailoring of anticancer therapies. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in cancer progression, not only because of its antioxidant activity but also because it establishes cross-talk with several oncogenic pathways, including Heat Shock Factor1 (HSF1), mammalian target of rapamycin (mTOR), and mutant (mut) p53. Moreover, the involvement of NRF2 in gammaherpesvirus-driven carcinogenesis is particularly interesting. These viruses indeed hijack the NRF2 pathway to sustain the survival of tumor cells in which they establish a latent infection and to avoid a too-high increase of reactive oxygen species (ROS) when these cancer cells undergo treatments that induce viral replication. Interestingly, NRF2 activation may prevent gammaherpesvirus-driven oncogenic transformation, highlighting how manipulating the NRF2 pathway in the different phases of gammaherpesvirus-mediated carcinogenesis may lead to different outcomes. This review will highlight the mechanistic interplay between NRF2 and some oncogenic pathways and its involvement in gammaherpesviruses biology to recapitulate published evidence useful for potential application in cancer therapy.

Keywords:  KEAP1; NFkB; NRF2; STAT3; apoptosis; autophagy; cancer therapy; chemoresistance; gammaherpesviruses; inflammation; mTOR; oxidative stress; p21; p53; p62/SQSTM1; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/ijms24010595
Theranostics. 2023 ;13(2): 704-723

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.

Ke Xu, Jie Ma, Sean R R Hall, Ren-Wang Peng, Haitang Yang, Feng Yao.

  The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.

Keywords:  KEAP1-NRF2 signaling; bioinformatics; metabolic reprogramming; non-small cell lung cancer; therapeutic vulnerabilities; tumor immune microenvironment

DOI:  https://doi.org/10.7150/thno.80184
Toxicol Appl Pharmacol. 2023 Jan 09. pii: S0041-008X(23)00013-3. [Epub ahead of print]460 116375

Inhibitors of Keap1-Nrf2 protein-protein interaction reduce estrogen responsive gene expression and oxidative stress in estrogen receptor-positive breast cancer.

Tingying Xie, Husam Zahid, Ahmed R Ali, Ryan Joyce, Ge Yang, Cassandra Winz, Yicong Le, Renping Zhou, Philip Furmanski, Longqin Hu, Nanjoo Suh.

  Estrogen contributes to the development of breast cancer through estrogen receptor (ER) signaling and by generating genotoxic metabolites that cause oxidative DNA damage. To protect against oxidative stress, cells activate nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream cytoprotective genes that initiate antioxidant responses and detoxify xenobiotics. Nrf2 activation occurs by inhibiting the protein-protein interaction (PPI) between Nrf2 and its inhibitor Keap1, which otherwise targets Nrf2 for ubiquitination and destruction. In this study, we examined a series of novel direct inhibitors of Keap1-Nrf2 PPI in their role in promoting the availability of Nrf2 for antioxidant activity and attenuating estrogen-mediated responses in breast cancer. ER-positive human breast cancer cells MCF-7 were treated with 17β-estradiol (E2) in the presence or absence of selected Keap1-Nrf2 PPI inhibitors. Keap1-Nrf2 PPI inhibitors suppressed the mRNA and protein levels of estrogen responsive genes induced by E2 exposure, such as PGR. Keap1-Nrf2 PPI inhibitors caused significant activation of Nrf2 target genes. E2 decreased the mRNA and protein level of the Nrf2 target gene NQO1, and the Keap1-Nrf2 PPI inhibitors reversed this effect. The reversal of E2 action by these compounds was not due to binding to ER as ER antagonists. Further, a selected compound attenuated oxidative stress induced by E2, determined by the level of a biomarker 8-oxo-deoxyguanosine. These findings suggest that the Keap1-Nrf2 PPI inhibitors have potent antioxidant activity by activating Nrf2 pathways and inhibit E2-induced gene and protein expression. These compounds may serve as potential chemopreventive agents in estrogen-stimulated breast cancer.

Keywords:  Breast cancer; Estrogen; Estrogen receptor; Keap1; Nrf2

DOI:  https://doi.org/10.1016/j.taap.2023.116375
Trends Pharmacol Sci. 2023 Jan 09. pii: S0165-6147(22)00277-2. [Epub ahead of print]

Advances and challenges in therapeutic targeting of NRF2.

Albena T Dinkova-Kostova, Ian M Copple.

  Activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is emerging as an attractive therapeutic approach to counteract oxidative stress, inflammation, and metabolic imbalances. These processes underpin many chronic pathologies with unmet therapeutic needs, including neurodegenerative disorders and metabolic diseases. As the NRF2 field transitions into the clinical phase of its evolution, the need for an understanding of the factors influencing NRF2 pharmacology has never been greater. In this opinion article we describe the rationale for targeting NRF2, summarise the recent advances in drug development of NRF2 modulators, and reflect on the remaining challenges in realising the full clinical potential of NRF2 as a therapeutic target.

Keywords:  KEAP1; NRF2; chronic disease; electrophile; inflammation; oxidative stress

DOI:  https://doi.org/10.1016/j.tips.2022.12.003
Allergol Immunopathol (Madr). 2023 ;51(1): 54-62

Nrf2 regulates the expression of NOX1 in TNF-α-induced A549 cells.

Weijing Wu, Jiamin Zhang, Xiaoshan Su, Xiaoping Lin, Li Zhu, Zesen Zhuang, Chennan Liu, Zhixing Zhu, Yiming Zeng.

  Acute lung injury causes severe inflammation and oxidative stress in lung tissues. In this study, we analyzed the potential regulatory role of nuclear factor erythroid-2-related factor 2 (Nrf2) on NADPH oxidase 1 (NOX1) in tumor necrosis factor-α (TNF-α)-induced inflammation and oxidative stress in human type II alveolar epithelial cells. In this study, A549 cells were transfected with Nrf2 siRNA and overexpression vectors for 6 h before being induced by TNF-α for 24 h. TNF-α upregulated the expression of NOX1 and Nrf2 in A549 cells. Furthermore, overexpression of Nrf2 could reduce TNF-α-induced NF-κB mRNA and protein expression after transfection with the Nrf2 siRNA vector, and the levels of IL-6, IL-8, ROS, and malondialdehyde (MDA) in TNF-α-induced A549 cells increased, while the level of total antioxidation capability (T-AOC) decreased. On the other hand, the overexpression of Nrf2 decreased the levels of IL-6, IL-8, ROS, and MDA, while increasing T-AOC. The mRNA and protein levels of NOX1 were dramatically increased by TNF-α, while those changes were notably suppressed by Nrf2 overexpression. Further studies demonstrated that Nrf2 suppressed NOX1 transcription by binding to the -1199 to -1189 bp (ATTACACAGCA) region of the NOX1 promoter in TNF-α-stimulated A549 cells. Our study suggests that Nrf2 may bind to and regulate NOX1 expression to antagonize TNF-α-induced inflammatory reaction and oxidative stress in A549 cells.

Keywords:  Acute Lung Injury; NOX1; Nrf2; Oxidative Stress; TNF-α

DOI:  https://doi.org/10.15586/aei.v51i1.732
Hum Exp Toxicol. 2023 Jan-Dec;42:42 9603271221149663

Mitochondrial ROS induced by ML385, an Nrf2 inhibitor aggravates the ferroptosis induced by RSL3 in human lung epithelial BEAS-2B cells.

Indra Putra Taufani, Jiro Hasegawa Situmorang, Rifki Febriansah, Sri Tasminatun, Sunarno Sunarno, Liang-Yo Yang, Yi-Ting Chiang, Chih-Yang Huang.

  Ferroptosis is a new type of cell death marked by iron and lipid ROS accumulation. GPX4 is one of the glutathione peroxidases known to regulate ferroptosis tightly. On the other hand, Nrf2 also plays a vital role in ferroptosis as it targets genes related to oxidant defense. Herein, we employed beas-2 human epithelial cells treated with a low concentration of RSL3 to induce ferroptosis. To study the protective role of Nrf2, we used ML385 as its specific inhibitor. A combination of ML385 and a low concentration of RSL3 synergistically induced more toxicity to RSL3. Furthermore, we found that mitochondrial ROS is elevated in ML385 and RSL3 combination group. In addition, Mito TEMPOL application successfully prevents the upregulation of mitochondrial ROS, lipid ROS, reduces the toxicity of RSL3, restores the antioxidant capacity of the cells, and mitochondrial functions reflected by mitochondrial membrane potential and mitochondrial oxidative phosphorylation system (OXPHOS) expression. Altogether, our study demonstrated that Nrf2 inhibition by ML385 induces more toxicity when combined with RSL3 through the elevation of mitochondrial ROS and disruption of mitochondrial function.

Keywords:  Ferroptosis; GPX4; Mito TEMPOL; Nrf2 inhibition; OXPHOS; RSL3; mitochondrial ROS

DOI:  https://doi.org/10.1177/09603271221149663
Cancers (Basel). 2022 Dec 28. pii: 172. [Epub ahead of print]15(1):

Anti-Anaplastic Thyroid Cancer (ATC) Effects and Mechanisms of PLX3397 (Pexidartinib), a Multi-Targeted Tyrosine Kinase Inhibitor (TKI).

Jingtao Luo, Yun Wang, Lingkun Zhao, Chunli Wang, Ze Zhang.

  Background Anaplastic thyroid cancer (ATC) is the greatest lethal thyroid neoplasm with a low incidence and lacks an effective treatment strategy and standardized treatment protocol. PLX3397 (Pexidartinib) is an FDA-approved multitarget tyrosine kinase inhibitor. The research is designed to explore the possible anti-proliferative activity of pexidartinib on ATC, as well as its related molecular mechanisms. Methods The cell viability was assessed by CCK-8, LDH release, colony formation, and EdU detection assays. Apoptosis and the alteration on cell cycle arrest were characterized by flow cytometry (FCM). ER stress was evaluated by immunofluorescence (IF). ROS levels were determined by flow cytometry. Western blot assays were conducted to evaluate changes in key molecules related to apoptosis and ER stress. The ATC xenografts model was established, and immunohistochemistry was performed to validate the anti-ATC effects of pexidartinib in vivo. Results Pexidartinib significantly inhibited ATC cell proliferation and induced apoptosis and cell cycle arrest. Moreover, pexidartinib potently induced ER stress and elevated ROS in ATC cells, and the apoptotic cells and ER stress in ATC after administration of pexidartinib could be reversed by an ER stress inhibitor and ROS scavenger, respectively. Furthermore, pexidartinib treatment induced Nrf2 accumulation in nuclei and reduced the interaction of Nrf2 with Keap-1, and knockdown of Nrf2 enhanced the anti-ATC effects of pexidartinib in vitro. In addition, pexidartinib significantly inhibited ATC xenograft growth and proliferation in vivo, and the combination of ML385, an Nrf2 inhibitor, potently enhanced the anti-ATC effects of pexidartinib in vivo. Conclusion Our findings suggest pexidartinib is a potential agent for treating ATC. Co-administration with an Nrf2 inhibitor is an effective synergistic strategy.

Keywords:  Nrf2; PLX3397 (Pexidartinib); anaplastic thyroid cancer (ATC); endoplasmic reticulum (ER) stress; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/cancers15010172