|
1
|
Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
Collapse
Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
| |
Collapse
|
|
2
|
Chen C, Chen M, Wen T, Awasthi P, Carrillo ND, Anderson RA, Cryns VL. Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.10.26.564194. [PMID: 37961303 PMCID: PMC10634847 DOI: 10.1101/2023.10.26.564194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase γ (PIPKIγ), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) to NRF2. PtdIns(4,5)P 2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKIγ or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIγ and HSP27 as drug targets to destabilize NRF2 in cancer. In brief Phosphoinositides are coupled to NRF2 by PIPKIγ, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.
Collapse
|
|
3
|
Moubarak MM, Pagano Zottola AC, Larrieu CM, Cuvellier S, Daubon T, Martin OCB. Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review. Neurooncol Adv 2024; 6:vdad160. [PMID: 38221979 PMCID: PMC10785770 DOI: 10.1093/noajnl/vdad160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024] Open
Abstract
Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species. The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade 4 glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2's dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.
Collapse
Affiliation(s)
- Maya M Moubarak
- University of Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France
| | | | | | | | - Thomas Daubon
- University of Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France
| | | |
Collapse
|
|
4
|
Pillai R, Hayashi M, Zavitsanou AM, Papagiannakopoulos T. NRF2: KEAPing Tumors Protected. Cancer Discov 2022; 12:625-643. [PMID: 35101864 DOI: 10.1158/2159-8290.cd-21-0922] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/22/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022]
Abstract
The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance. SIGNIFICANCE: Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.
Collapse
Affiliation(s)
- Ray Pillai
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, VA New York Harbor Healthcare System, New York, New York.,Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Perlmutter Cancer Center, New York University School of Medicine, New York, New York
| | - Makiko Hayashi
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York
| | - Anastasia-Maria Zavitsanou
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York
| | - Thales Papagiannakopoulos
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York.
| |
Collapse
|
|
5
|
Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol 2022; 14:38-54. [PMID: 35116102 PMCID: PMC8790418 DOI: 10.4251/wjgo.v14.i1.38] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
Collapse
Affiliation(s)
- Nirosha J Murugan
- Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
| |
Collapse
|
|
6
|
Hamada S, Matsumoto R, Masamune A. HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14020411. [PMID: 35053572 PMCID: PMC8773475 DOI: 10.3390/cancers14020411] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/13/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic cancer progression involves interactions between cancer cells and stromal cells in harsh tumor microenvironments, which are characterized by hypoxia, few nutrients, and oxidative stress. Clinically, cancer cells overcome therapeutic interventions, such as chemotherapy and radiotherapy, to continue to survive. Activation of the adaptation mechanism is required for cancer cell survival under these conditions, and it also contributes to the acquisition of the malignant phenotype. Stromal cells, especially pancreatic stellate cells, play a critical role in the formation of a cancer-promoting microenvironment. We here review the roles of key molecules, hypoxia inducible factor-1 and KEAP1-NRF2, in stress response mechanisms for the adaptation to hypoxia and oxidative stress in pancreatic cancer cells and stellate cells. Various cancer-promoting properties associated with these molecules have been identified, and they might serve as novel therapeutic targets in the future. Abstract Pancreatic cancer is intractable due to early progression and resistance to conventional therapy. Dense fibrotic stroma, known as desmoplasia, is a characteristic feature of pancreatic cancer, and develops through the interactions between pancreatic cancer cells and stromal cells, including pancreatic stellate cells. Dense stroma forms harsh tumor microenvironments characterized by hypoxia, few nutrients, and oxidative stress. Pancreatic cancer cells as well as pancreatic stellate cells survive in the harsh microenvironments through the altered expression of signaling molecules, transporters, and metabolic enzymes governed by various stress response mechanisms. Hypoxia inducible factor-1 and KEAP1-NRF2, stress response mechanisms for hypoxia and oxidative stress, respectively, contribute to the aggressive behaviors of pancreatic cancer. These key molecules for stress response mechanisms are activated, both in pancreatic cancer cells and in pancreatic stellate cells. Both factors are involved in the mutual activation of cancer cells and stellate cells, by inducing cancer-promoting signals and their mediators. Therapeutic interventions targeting these pathways are promising approaches for novel therapies. In this review, we summarize the roles of stress response mechanisms, focusing on hypoxia inducible factor-1 and KEAP1-NRF2, in pancreatic cancer. In addition, we discuss the potential of targeting these molecules for the treatment of pancreatic cancer.
Collapse
|
|
7
|
Focal Parenchymal Atrophy of the Pancreas Is Frequently Observed on Pre-Diagnostic Computed Tomography in Patients with Pancreatic Cancer: A Case-Control Study. Diagnostics (Basel) 2021; 11:diagnostics11091693. [PMID: 34574034 PMCID: PMC8471718 DOI: 10.3390/diagnostics11091693] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/06/2021] [Accepted: 09/14/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) accounts for the majority of all pancreatic cancers and is highly lethal. Focal parenchymal atrophy (FPA) of the pancreas has been reported as a characteristic imaging finding of early PDAC. Here, we reviewed 76 patients with PDAC who underwent computed tomography (CT) between 6 months and 3 years before PDAC diagnosis, as well as 76 sex- and age-matched controls without PDAC on CT examinations separated by at least 5 years. FPA was observed corresponding to the location of the subsequent tumor on pre-diagnostic CT in 14/44 (31.8%) patients between 6 months and 1 year, 14/51 (27.5%) patients between 1 and 2 years, and 9/41 (22.0%) patients between 2 and 3 years before PDAC diagnosis. Overall, FPA was more frequently observed in patients with PDAC (26/76; 34.2%) on pre-diagnostic CT than that in controls (3/76; 3.9%) (p < 0.001). FPA was observed before the appearance of cut-off/dilatation of the main pancreatic duct, suggesting that FPA might be the earliest sign of PDAC. FPA was less frequently found in tumors in the pancreatic head (3/27; 11.1%) than in those in the body (14/30; 46.7%) or tail (9/19; 47.4%). FPA may predict the subsequent PDAC diagnosis, serving as an important imaging sign for the early diagnosis of pancreatic cancer.
Collapse
|
|
8
|
Hamada S, Matsumoto R, Tanaka Y, Taguchi K, Yamamoto M, Masamune A. Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition. Int J Mol Sci 2021; 22:1870. [PMID: 33672789 PMCID: PMC7918355 DOI: 10.3390/ijms22041870] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.
Collapse
Affiliation(s)
- Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
| | - Ryotaro Matsumoto
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
| | - Yu Tanaka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
| | - Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; (K.T.); (M.Y.)
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; (K.T.); (M.Y.)
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
| |
Collapse
|
|
9
|
Fuloria S, Subramaniyan V, Karupiah S, Kumari U, Sathasivam K, Meenakshi DU, Wu YS, Sekar M, Chitranshi N, Malviya R, Sudhakar K, Bajaj S, Fuloria NK. Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer. Antioxidants (Basel) 2021; 10:128. [PMID: 33477494 PMCID: PMC7831054 DOI: 10.3390/antiox10010128] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/09/2021] [Accepted: 01/13/2021] [Indexed: 12/17/2022] Open
Abstract
Evidence suggests that reactive oxygen species (ROS) mediate tissue homeostasis, cellular signaling, differentiation, and survival. ROS and antioxidants exert both beneficial and harmful effects on cancer. ROS at different concentrations exhibit different functions. This creates necessity to understand the relation between ROS, antioxidants, and cancer, and methods for detection of ROS. This review highlights various sources and types of ROS, their tumorigenic and tumor prevention effects; types of antioxidants, their tumorigenic and tumor prevention effects; and abnormal ROS detoxification in cancer; and methods to measure ROS. We conclude that improving genetic screening methods and bringing higher clarity in determination of enzymatic pathways and scale-up in cancer models profiling, using omics technology, would support in-depth understanding of antioxidant pathways and ROS complexities. Although numerous methods for ROS detection are developing very rapidly, yet further modifications are required to minimize the limitations associated with currently available methods.
Collapse
Affiliation(s)
| | - Vetriselvan Subramaniyan
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | | | - Usha Kumari
- Faculty of Medicine, AIMST University, Kedah 08100, Malaysia;
| | | | | | - Yuan Seng Wu
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | - Mahendran Sekar
- Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh 30450, Malaysia;
| | - Nitin Chitranshi
- Faculty of Medicine and Human Sciences, Maquarie University, North Ryde, NSW 2109, Australia;
| | - Rishabha Malviya
- Department of Pharmacy, SMAS, Galgotias University, Greater Noida 203201, India;
| | - Kalvatala Sudhakar
- School of Pharmaceutical Sciences (LIT-Pharmacy), Lovely Professional University, Jalandhar 144411, India;
| | - Sakshi Bajaj
- Delhi Institute of Pharmaceutical Science and Research, Pushp Vihar, New Delhi 110017, India;
| | | |
Collapse
|
|
10
|
Takahashi N, Cho P, Selfors LM, Kuiken HJ, Kaul R, Fujiwara T, Harris IS, Zhang T, Gygi SP, Brugge JS. 3D Culture Models with CRISPR Screens Reveal Hyperactive NRF2 as a Prerequisite for Spheroid Formation via Regulation of Proliferation and Ferroptosis. Mol Cell 2020; 80:828-844.e6. [PMID: 33128871 PMCID: PMC7718371 DOI: 10.1016/j.molcel.2020.10.010] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/03/2020] [Accepted: 10/04/2020] [Indexed: 01/09/2023]
Abstract
Cancer-associated mutations that stabilize NRF2, an oxidant defense transcription factor, are predicted to promote tumor development. Here, utilizing 3D cancer spheroid models coupled with CRISPR-Cas9 screens, we investigate the molecular pathogenesis mediated by NRF2 hyperactivation. NRF2 hyperactivation was necessary for proliferation and survival in lung tumor spheroids. Antioxidant treatment rescued survival but not proliferation, suggesting the presence of distinct mechanisms. CRISPR screens revealed that spheroids are differentially dependent on the mammalian target of rapamycin (mTOR) for proliferation and the lipid peroxidase GPX4 for protection from ferroptosis of inner, matrix-deprived cells. Ferroptosis inhibitors blocked death from NRF2 downregulation, demonstrating a critical role of NRF2 in protecting matrix-deprived cells from ferroptosis. Interestingly, proteomics analyses show global enrichment of selenoproteins, including GPX4, by NRF2 downregulation, and targeting NRF2 and GPX4 killed spheroids overall. These results illustrate the value of spheroid culture in revealing environmental or spatial differential dependencies on NRF2 and reveal exploitable vulnerabilities of NRF2-hyperactivated tumors.
Collapse
Affiliation(s)
- Nobuaki Takahashi
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Cancer Center, Boston, MA 02115, USA.
| | - Patricia Cho
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Cancer Center, Boston, MA 02115, USA
| | - Laura M Selfors
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Cancer Center, Boston, MA 02115, USA
| | - Hendrik J Kuiken
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Cancer Center, Boston, MA 02115, USA
| | - Roma Kaul
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Cancer Center, Boston, MA 02115, USA
| | - Takuro Fujiwara
- Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto 615-8510, Japan
| | - Isaac S Harris
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Cancer Center, Boston, MA 02115, USA
| | - Tian Zhang
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Joan S Brugge
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Cancer Center, Boston, MA 02115, USA.
| |
Collapse
|
|
11
|
Liang X, Hu C, Liu C, Yu K, Zhang J, Jia Y. Dihydrokaempferol (DHK) ameliorates severe acute pancreatitis (SAP) via Keap1/Nrf2 pathway. Life Sci 2020; 261:118340. [PMID: 32860805 DOI: 10.1016/j.lfs.2020.118340] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/18/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022]
Abstract
Severe acute pancreatitis (SAP) is a non-bacterial inflammatory disease that clinically causes a very high rate of mortality. Dihydrokaempferol (DHK) is a natural flavonoid extracted from Bauhinia championii. Our research aimed to establish the treatment function of DHK on SAP-induced pancreas injury and delve into its potential mechanism. In this study, SAP was induced by caerulein (CER) and Lipopolysaccharide (LPS). DHK was administered orally at different doses of 20, 40, or 80 mg/kg. Results from serum amylase/lipase, pancreas hematoxylin-eosin staining technique, pancreas malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) showed the therapeutic effect of DHK in a mice SAP model. MTT revealed DHK alleviated CER + LPS induced cytotoxicity in a dose-dependent manner in the pancreatic acinar cells of mice. Next, we verified DHK suppressed the level of Keap1 and promoted transcriptional activation of nuclear Nrf2 in the presence of CER + LPS. The molecular docking study suggested that there is a potential interaction between DHK and Keap1. To further look at the role of Keap1 using in vitro and in vivo models, Keap1 overexpression adenovirus (ad-Keap1) was performed. The results revealed that ad-Keap1suppressed the nuclear translocation of Nrf2 which is enhanced by DHK, and suppressed the antioxidative functionality of DHK both in mice and cell models. Collectively, this research demonstrated that DHK bettered the SAP induced pancreas injury by regulating the Keap1/Nrf2 pathway and regulating oxidative stress injury.
Collapse
Affiliation(s)
- Xiaoqiang Liang
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Cheng Hu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Congying Liu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Kui Yu
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jingzhe Zhang
- Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Yiqun Jia
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| |
Collapse
|
|
12
|
Smolková K, Mikó E, Kovács T, Leguina-Ruzzi A, Sipos A, Bai P. Nuclear Factor Erythroid 2-Related Factor 2 in Regulating Cancer Metabolism. Antioxid Redox Signal 2020; 33:966-997. [PMID: 31989830 PMCID: PMC7533893 DOI: 10.1089/ars.2020.8024] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Significance: Nuclear factor erythroid 2 (NFE2)-related factor 2 (NFE2L2, or NRF2) is a transcription factor predominantly affecting the expression of antioxidant genes. NRF2 plays a significant role in the control of redox balance, which is crucial in cancer cells. NRF2 activation regulates numerous cancer hallmarks, including metabolism, cancer stem cell characteristics, tumor aggressiveness, invasion, and metastasis formation. We review the molecular characteristics of the NRF2 pathway and discuss its interactions with the cancer hallmarks previously listed. Recent Advances: The noncanonical activation of NRF2 was recently discovered, and members of this pathway are involved in carcinogenesis. Further, cancer-related changes (e.g., metabolic flexibility) that support cancer progression were found to be redox- and NRF2 dependent. Critical Issues: NRF2 undergoes Janus-faced behavior in cancers. The pro- or antineoplastic effects of NRF2 are context dependent and essentially based on the specific molecular characteristics of the cancer in question. Therefore, systematic investigation of NRF2 signaling is necessary to clarify its role in cancer etiology. The biggest challenge in the NRF2 field is to determine which cancers can be targeted for better clinical outcomes. Further, large-scale genomic and transcriptomic studies are missing to correlate the clinical outcome with the activity of the NRF2 system. Future Directions: To exploit NRF2 in a clinical setting in the future, the druggable members of the NRF2 pathway should be identified. In addition, it will be important to study how the modulation of the NRF2 system interferes with cytostatic drugs and their combinations.
Collapse
Affiliation(s)
- Katarína Smolková
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Prague, Czech Republic
| | - Edit Mikó
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.,MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary
| | - Tünde Kovács
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Alberto Leguina-Ruzzi
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Prague, Czech Republic
| | - Adrienn Sipos
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Bai
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.,MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary.,Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary
| |
Collapse
|
|
13
|
Kong H, Reczek CR, McElroy GS, Steinert EM, Wang T, Sabatini DM, Chandel NS. Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species. SCIENCE ADVANCES 2020; 6:6/45/eabb7272. [PMID: 33148642 PMCID: PMC7673681 DOI: 10.1126/sciadv.abb7272] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 09/14/2020] [Indexed: 05/21/2023]
Abstract
Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR-Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I was deleterious in the presence of the mitochondria-targeted antioxidant mito-vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. This was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness.
Collapse
Affiliation(s)
- Hyewon Kong
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Colleen R Reczek
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Gregory S McElroy
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Elizabeth M Steinert
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Tim Wang
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
| | - David M Sabatini
- Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Broad Institute, Cambridge, MA 02142, USA
- The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Navdeep S Chandel
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
| |
Collapse
|
|
14
|
Kopacz A, Kloska D, Forman HJ, Jozkowicz A, Grochot-Przeczek A. Beyond repression of Nrf2: An update on Keap1. Free Radic Biol Med 2020; 157:63-74. [PMID: 32234331 PMCID: PMC7732858 DOI: 10.1016/j.freeradbiomed.2020.03.023] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 03/04/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022]
Abstract
Nrf2 (NFE2L2 - nuclear factor (erythroid-derived 2)-like 2) is a transcription factor, which is repressed by interaction with a redox-sensitive protein Keap1 (Kelch-like ECH-associated protein 1). Deregulation of Nrf2 transcriptional activity has been described in the pathogenesis of multiple diseases, and the Nrf2/Keap1 axis has emerged as a crucial modulator of cellular homeostasis. Whereas the significance of Nrf2 in the modulation of biological processes has been well established and broadly discussed in detail, the focus on Keap1 rarely goes beyond the regulation of Nrf2 activity and redox sensing. However, recent studies and scrutinized analysis of available data point to Keap1 as an intriguing and potent regulator of cellular function. This review aims to shed more light on Keap1 structure, interactome, regulation and non-canonical functions, thereby enhancing its significance in cell biology. We also intend to highlight the impact of balance between Keap1 and Nrf2 in the maintenance of cellular homeostasis.
Collapse
Affiliation(s)
- Aleksandra Kopacz
- Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, 30-387, Krakow, Poland
| | - Damian Kloska
- Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, 30-387, Krakow, Poland
| | - Henry Jay Forman
- Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089-0191, USA
| | - Alicja Jozkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, 30-387, Krakow, Poland
| | - Anna Grochot-Przeczek
- Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, 30-387, Krakow, Poland.
| |
Collapse
|
|
15
|
Harris IS, DeNicola GM. The Complex Interplay between Antioxidants and ROS in Cancer. Trends Cell Biol 2020; 30:440-451. [PMID: 32303435 DOI: 10.1016/j.tcb.2020.03.002] [Citation(s) in RCA: 386] [Impact Index Per Article: 77.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 02/08/2023]
Abstract
Reactive oxygen species (ROS) play important roles in tissue homeostasis, cellular signaling, differentiation, and survival. In this review, we discuss the types ofROS, their impact on cellular processes, and their pro- and antitumorigenic effects. Further, we discuss recent advances in our understanding of both endogenous and exogenous antioxidants in tumorigenic processes. Finally, wediscuss how aberrant activation of antioxidant programs by the transcription factor NFE2-related factor 2 (NRF2) influences tumorigenesis and metastasis, and where the current gaps in our knowledge remain.
Collapse
Affiliation(s)
- Isaac S Harris
- Department of Biomedical Genetics and Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
| | - Gina M DeNicola
- Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
| |
Collapse
|
|
16
|
Wu WL, Papagiannakopoulos T. The Pleiotropic Role of the KEAP1/NRF2 Pathway in Cancer. ANNUAL REVIEW OF CANCER BIOLOGY 2020. [DOI: 10.1146/annurev-cancerbio-030518-055627] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The unregulated proliferative capacity of many tumors is dependent on dysfunctional nutrient utilization and ROS (reactive oxygen species) signaling to sustain a deranged metabolic state. Although it is clear that cancers broadly rely on these survival and signaling pathways, how they achieve these aims varies dramatically. Mutations in the KEAP1/NRF2 pathway represent a potent cancer adaptation to exploit native cytoprotective pathways that involve both nutrient metabolism and ROS regulation. Despite activating these advantageous processes, mutations within KEAP1/ NRF2 are not universally selected for across cancers and instead appear to interact with particular tumor driver mutations and tissues of origin. Here, we highlight the relationship between the KEAP1/NRF2 signaling axis and tumor biology with a focus on genetic mutation, metabolism, immune regulation, and treatment implications and opportunities. Understanding the dysregulation of KEAP1 and NRF2 provides not only insight into a commonly mutated tumor suppressor pathway but also a window into the factors dictating the development and evolution of many cancers.
Collapse
Affiliation(s)
- Warren L. Wu
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | | |
Collapse
|
|
17
|
Qin JJ, Cheng XD, Zhang J, Zhang WD. Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review. Cell Commun Signal 2019; 17:121. [PMID: 31511020 PMCID: PMC6740038 DOI: 10.1186/s12964-019-0435-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 09/02/2019] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.
Collapse
Affiliation(s)
- Jiang-Jiang Qin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China. .,Zhejiang Cancer Hospital, Hangzhou, 310022, China.
| | | | - Jia Zhang
- Shanxi Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Wei-Dong Zhang
- School of Pharmacy, Naval Medical University, 325 Guohe Road, Yangpu District, Shanghai, 200433, China. .,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
|
18
|
Du J, He Y, Wu W, Li P, Chen Y, Hu Z, Han Y. Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer. J Pharm Pharmacol 2019; 71:196-205. [PMID: 30604411 DOI: 10.1111/jphp.12941] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 05/19/2018] [Indexed: 01/04/2023]
Abstract
OBJECTIVES Chemotheraputic drug resistance is a critical factor associated with the poor survival in advanced/metastatic pancreatic cancer (PC) patients. METHODS Human pancreatic cell lines Capan-1 and BXPC-3 were cultured with different concentrations of erlotinib (0, 10, 50, and 100 μm) for 48 h. The relative cell viability and apoptosis was detected using MTT assays and flow cytometry apoptosis analysis, respectively. Transfection of pcDNA-EphA2, si-EphA2 and miR-124 mimic/inhibitor was used to modulate the intracellular level of EphA2 and miR-124. The interaction between miR-124 and the 3'UTR of EphA2 was explored using dual luciferase reporter assay. KEY FINDINGS Compared with BXPC-3 cells, Capan-1 cells showed resistance to differential concentration treatment of erlotinib. The expression of EphA-2 was significantly increased and the expression of miR-124 was significantly decreased in Capan-1 cells. Overexpressing EphA2 induced resistance of BXPC-3 cells to erlotinib treatment. And EphA2 was identified as a novel target gene for miR-124. MiR-124 overexpression was able to sensitize the response of Capan-1 cells to erlotinib through inhibiting EphA2. Furthermore, both miR-124 overexpression and EphA2 inhibition sensitized Capan-1 cells to erlotinib in xenograft model. CONCLUSIONS Our study demonstrated that EphA2 rescued by miR-124 downregulation conferred the erlotinib resistance of PC cell Capan-1 with K-RAS mutation.
Collapse
Affiliation(s)
- Jing Du
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.,People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yuanqiao He
- Department of Laboratory Animal Science, Nanchang University, Nanchang, Jiangxi, China
| | - Weiquan Wu
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.,People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Peng Li
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.,People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Youwei Chen
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.,People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhiming Hu
- People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.,Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.,Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yong Han
- People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, Zhejiang, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| |
Collapse
|
|
19
|
Kitamura H, Motohashi H. NRF2 addiction in cancer cells. Cancer Sci 2018; 109:900-911. [PMID: 29450944 PMCID: PMC5891176 DOI: 10.1111/cas.13537] [Citation(s) in RCA: 202] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/10/2018] [Indexed: 12/13/2022] Open
Abstract
The Kelch‐like ECH‐associated protein 1/nuclear factor erythroid‐derived 2‐like 2 (KEAP1‐NRF2) system is a pivotal defense mechanism against oxidative and electrophilic stress. Although transient NRF2 activation in response to stress is beneficial for health, persistent NRF2 activation in cancer cells has deleterious effects on cancer‐bearing hosts by conferring therapeutic resistance and aggressive tumorigenic activity on cancer cells. Because NRF2 increases the antioxidant and detoxification capability of cancer cells, persistently high levels of NRF2 activity enhance therapeutic resistance of cancer cells. NRF2 also drives metabolic reprogramming to establish cellular metabolic processes that are advantageous for cell proliferation in cooperation with other oncogenic pathways. As a result of these advantages, cancer cells with persistent activation of NRF2 often develop “NRF2 addiction” and show malignant phenotypes leading to poor prognoses in cancer patients. Inhibition of NRF2 is a promising therapeutic approach for NRF2‐addicted cancers and NRF2 inhibitors are being actively developed. However, giving systemic NRF2 inhibitors might have undesirable effects on cancer‐bearing hosts, considering the central roles of NRF2 in cytoprotection. To avoid these side‐effects, new therapeutic targets besides NRF2 for NRF2‐addicted cancers have been actively explored. This review introduces recent studies describing the development and characterization of NRF2‐addicted cancers, as well as their potential therapeutic targets. Expected advances in diagnostic and therapeutic interventions for NRF2‐addicted cancers are also discussed.
Collapse
Affiliation(s)
- Hiroshi Kitamura
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Hozumi Motohashi
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| |
Collapse
|