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1
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Wang K, Sun M, Liu S, Wang R, Liu H, Qian F. Albumin-conjugated flumethasone for targeting and normalization of pancreatic stellate cells. J Control Release 2025; 380:994-1004. [PMID: 39983925 DOI: 10.1016/j.jconrel.2025.02.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 01/16/2025] [Accepted: 02/18/2025] [Indexed: 02/23/2025]
Abstract
The tumor microenvironment (TME) plays a critical role in the poor clinical outlook for pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic stellate cells (PSC) drive the complex interactions within the TME, resulting in a microenvironment that is resistant to chemotherapy and tolerant to the immune system, thereby promoting tumor growth. Effective deactivation of PSC is vital in treating pancreatic cancer. However, previous studies have only focused on limited changes in PSC phenotype without comprehensively analysing their overall function. Our transcriptome analysis identified agents capable of modulating multiple biological functions of PSC, including fibrosis, extracellular matrix generation, and the secretion of cytokines and immune factors. Through this comprehensive assessment, we discovered that flumethasone (Flu) effectively deactivates PSC. This glucocorticoid analogue remodels the tumor microenvironment by regulating the secretomes of PSC and their interaction with tumor cells. Additionally, our research revealed that activated PSC exhibited heightened albumin endocytosis. As a result, we propose that albumin conjugation could serve as an effective targeted drug delivery approach for PSC. Our findings also demonstrate that albumin-conjugated Flu maintained reprogramming capabilities in stromal cells, and enhanced the efficacy of chemotherapy in orthotopic mouse models of PDAC and KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) pancreatic tumor allograft mouse model. Our investigation into the mechanism of PSC deactivation by flumethasone has revealed its potential for clinical cancer treatment through its effects on the tumor microenvironment. Furthermore, the conjugation of flumethasone to albumin enhances its safety and targeted delivery, offering a promising approach for PSC-targeted drug application in pancreatic cancer treatment.
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Affiliation(s)
- Kaixin Wang
- School of Pharmaceutical Sciences, Beijing Frontier Research Center for Biological Structure, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, PR China
| | - Mengnan Sun
- School of Pharmaceutical Sciences, Beijing Frontier Research Center for Biological Structure, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, PR China
| | - Shiyu Liu
- School of Pharmaceutical Sciences, Beijing Frontier Research Center for Biological Structure, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, PR China
| | - Rui Wang
- School of Pharmaceutical Sciences, Beijing Frontier Research Center for Biological Structure, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, PR China
| | - Huiqin Liu
- Quaerite Biopharm Research, Beijing, China
| | - Feng Qian
- School of Pharmaceutical Sciences, Beijing Frontier Research Center for Biological Structure, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, PR China.
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2
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Greenwood HE, Barber AR, Edwards RS, Tyrrell WE, George ME, Dos Santos SN, Baark F, Tanc M, Khalil E, Falzone A, Ward NP, DeBlasi JM, Torrente L, Soni PN, Pearce DR, Firth G, Smith LM, Vilhelmsson Timmermand O, Huebner A, Swanton C, Hynds RE, DeNicola GM, Witney TH. Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography. Nat Commun 2024; 15:10484. [PMID: 39690148 PMCID: PMC11652680 DOI: 10.1038/s41467-024-54852-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 11/21/2024] [Indexed: 12/19/2024] Open
Abstract
Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system xc- radiotracer, [18F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.
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Affiliation(s)
- Hannah E Greenwood
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Abigail R Barber
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Richard S Edwards
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Will E Tyrrell
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Madeleine E George
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Sofia N Dos Santos
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Friedrich Baark
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Muhammet Tanc
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Eman Khalil
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Aimee Falzone
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Nathan P Ward
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Janine M DeBlasi
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Laura Torrente
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Pritin N Soni
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - David R Pearce
- CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - George Firth
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | - Lydia M Smith
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK
| | | | - Ariana Huebner
- CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Charles Swanton
- CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Robert E Hynds
- CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Gina M DeNicola
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Timothy H Witney
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK.
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3
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Shan C, Wang Y, Wang Y. The Crosstalk between Autophagy and Nrf2 Signaling in Cancer: from Biology to Clinical Applications. Int J Biol Sci 2024; 20:6181-6206. [PMID: 39664581 PMCID: PMC11628323 DOI: 10.7150/ijbs.103187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/29/2024] [Indexed: 12/13/2024] Open
Abstract
Autophagy is a catabolic process that has been conserved throughout evolution, serving to degrade and recycle cellular components and damaged organelles. Autophagy is activated under various stress conditions, such as nutrient deprivation, viral infections, and genotoxic stress, and operates in conjunction with other stress response pathways to mitigate oxidative damage and maintain cellular homeostasis. One such pathway is the Nrf2-Keap1-ARE signaling axis, which functions as an intrinsic antioxidant defense mechanism and has been implicated in cancer chemoprevention, tumor progression, and drug resistance. Recent research has identified a link between impaired autophagy, mediated by the autophagy receptor protein p62, and the activation of the Nrf2 pathway. Specifically, p62 facilitates Keap1 degradation through selective autophagy, leading to the translocation of Nrf2 into the nucleus, where it transcriptionally activates downstream antioxidant enzyme expression, thus safeguarding cells from oxidative stress. Furthermore, Nrf2 regulates p62 transcription, so a positive feedback loop involving p62, Keap1, and Nrf2 is established, which amplifies the protective effects on cells. This paper aims to provide a comprehensive review of the roles of Nrf2 and autophagy in cancer progression, the regulatory interactions between the Nrf2 pathway and autophagy, and the potential applications of the Nrf2-autophagy signaling axis in cancer therapy.
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Affiliation(s)
- Chan Shan
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yuan Wang
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yin Wang
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
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4
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de Laat V, Topal H, Spotbeen X, Talebi A, Dehairs J, Idkowiak J, Vanderhoydonc F, Ostyn T, Zhao P, Jacquemyn M, Wölk M, Sablina A, Augustyns K, Vanden Berghe T, Roskams T, Daelemans D, Fedorova M, Topal B, Swinnen JV. Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer. Nat Commun 2024; 15:8540. [PMID: 39358362 PMCID: PMC11447004 DOI: 10.1038/s41467-024-52978-z] [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: 04/12/2023] [Accepted: 09/26/2024] [Indexed: 10/04/2024] Open
Abstract
A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.
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Affiliation(s)
- Vincent de Laat
- Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Halit Topal
- Abdominal Surgical Oncology, University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Xander Spotbeen
- Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Ali Talebi
- Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Jonas Dehairs
- Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Jakub Idkowiak
- Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Frank Vanderhoydonc
- Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Tessa Ostyn
- Department of Pathology, University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Peihua Zhao
- Laboratory for Mechanisms of Cell Transformation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
| | - Maarten Jacquemyn
- Molecular Genetics and Therapeutics in Virology and Oncology, Rega Institute for Medical Research, KU Leuven Department of Microbiology and Immunology, Leuven, Belgium
| | - Michele Wölk
- Center of Membrane Biochemistry and Lipid Research, Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
| | - Anna Sablina
- Laboratory for Mechanisms of Cell Transformation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
| | - Koen Augustyns
- Department of Pharmaceutical Sciences, Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium
| | - Tom Vanden Berghe
- Department of Biomedical Molecular Biology, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Tania Roskams
- Department of Pathology, University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Dirk Daelemans
- Molecular Genetics and Therapeutics in Virology and Oncology, Rega Institute for Medical Research, KU Leuven Department of Microbiology and Immunology, Leuven, Belgium
| | - Maria Fedorova
- Center of Membrane Biochemistry and Lipid Research, Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
| | - Baki Topal
- Abdominal Surgical Oncology, University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Johannes V Swinnen
- Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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5
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Riazi-Tabrizi N, Khalaj-Kondori M, Safaei S, Amini M, Hassanian H, Maghsoudi M, Hasani S, Baradaran B. NRF2 Suppression Enhances the Susceptibility of Pancreatic Cancer Cells, Miapaca-2 to Paclitaxel. Mol Biotechnol 2024; 66:2441-2454. [PMID: 37740817 DOI: 10.1007/s12033-023-00872-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 09/04/2023] [Indexed: 09/25/2023]
Abstract
Pancreatic cancer is one of the most deadly diseases, with a very high metastasis and low survival rate. High levels of NRF2 have been detected in numerous malignancies, including head, neck, lung, and colon cancers, promoting the expansion and survival of cancer cells and chemical resistance to stressful conditions and affecting the response to treatment. To evaluate the possibility that modulation of NRF2 expression could be effective in treating pancreatic cancer cells, we explored the effect of knockdown of the NRF2 gene by NRF2-specific siRNA and its influence in combination with paclitaxel on pancreatic cancer cells. Miapaca-2 cell line, due to the high expression of the NRF2 gene, was selected for this study. Then, Miapaca-2 cells in different groups were treated with NRF2 siRNA and paclitaxel separately and in combination. After that, cell viability was measured by MTT assay and apoptosis induction by Annexin V-FITC/PI staining test. Cell cycle and autophagy were examined by flow cytometry, and cell migration was assessed by wound-healing assay. Finally, the expression of genes involved in apoptosis, Bax, Caspase-3, Caspase-9, and genes related to migration pathway, MMP-2, and MMP-9 in different groups were measured using qRT-PCR. Combined use of NRF2-specific siRNA with paclitaxel significantly reduced NRF2 gene expression in pancreatic cancer cells. NRF2 siRNA transfection significantly reduced cell viability. In addition, paclitaxel combination therapy with NRF2 siRNA strengthens the anti-tumor effects, such as inhibiting cell migration and provoking apoptosis, and autophagy and the cell cycle arrest in the G2 phase. NRF2 suppression augmented the expression of Bax, Caspase-3, and Caspase-9 genes and lowered the expression of Bcl-2, MMP-2, and MMP-9 genes, which play crucial roles in the pathways of apoptosis and cell migration, respectively. NRF2 siRNA enhances the susceptibility of Miapaca-2 cells to paclitaxel in pancreatic cancer cells. Thereby, suppressing NRF2 in combination with paclitaxel can be a new and efficacious treatment approach in treating pancreatic cancer.
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Affiliation(s)
- Negin Riazi-Tabrizi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamidreza Hassanian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohadeseh Maghsoudi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Shima Hasani
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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6
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Hammad M, Salma R, Balosso J, Rezvani M, Haghdoost S. Role of Oxidative Stress Signaling, Nrf2, on Survival and Stemness of Human Adipose-Derived Stem Cells Exposed to X-rays, Protons and Carbon Ions. Antioxidants (Basel) 2024; 13:1035. [PMID: 39334694 PMCID: PMC11429097 DOI: 10.3390/antiox13091035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
Some cancers have a poor prognosis and often lead to local recurrence because they are resistant to available treatments, e.g., glioblastoma. Attempts have been made to increase the sensitivity of resistant tumors by targeting pathways involved in the resistance and combining it, for example, with radiotherapy (RT). We have previously reported that treating glioblastoma stem cells with an Nrf2 inhibitor increases their radiosensitivity. Unfortunately, the application of drugs can also affect normal cells. In the present study, we aim to investigate the role of the Nrf2 pathway in the survival and differentiation of normal human adipose-derived stem cells (ADSCs) exposed to radiation. We treated ADSCs with an Nrf2 inhibitor and then exposed them to X-rays, protons or carbon ions. All three radiation qualities are used to treat cancer. The survival and differentiation abilities of the surviving ADSCs were studied. We found that the enhancing effect of Nrf2 inhibition on cell survival levels was radiation-quality-dependent (X-rays > proton > carbon ions). Furthermore, our results indicate that Nrf2 inhibition reduces stem cell differentiation by 35% and 28% for adipogenesis and osteogenesis, respectively, using all applied radiation qualities. Interestingly, the results show that the cells that survive proton and carbon ion irradiations have an increased ability, compared with X-rays, to differentiate into osteogenesis and adipogenesis lineages. Therefore, we can conclude that the use of carbon ions or protons can affect the stemness of irradiated ADSCs at lower levels than X-rays and is thus more beneficial for long-time cancer survivors, such as pediatric patients.
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Affiliation(s)
- Mira Hammad
- Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP) UMR 6252, University of Caen Normandy, Cedex 04, F-14050 Caen, France
| | - Rima Salma
- Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP) UMR 6252, University of Caen Normandy, Cedex 04, F-14050 Caen, France
| | - Jacques Balosso
- Department of Radiation Oncology, Centre François Baclesse, F-14000 Caen, France
- Advanced Resource Center for HADrontherapy in Europe (ARCHADE), F-14000 Caen, France
| | - Mohi Rezvani
- Swiss Bioscience GmbH, Wagistrasse 27a, CH-8952 Schlieren, Switzerland
| | - Siamak Haghdoost
- Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP) UMR 6252, University of Caen Normandy, Cedex 04, F-14050 Caen, France
- Advanced Resource Center for HADrontherapy in Europe (ARCHADE), F-14000 Caen, France
- Le Laboratoire "Aliments, Bioprocédés, Toxicologie et Environnement (ABTE) UR 4651, ToxEMAC Team, University of Caen Normandy, Cedex 04, F-14050 Caen, France
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden
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7
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Ajuwon OR, Nsole-Biteghe FA, Ndong JD, Davids LM, Ajiboye BO, Brai B, Bamisaye FA, Falode JA, Odoh IM, Adegbite KI, Adegoke BO, Ntwasa M, Lebelo SL, Ayeleso AO. Nrf2-Mediated Antioxidant Response and Drug Efflux Transporters Upregulation as Possible Mechanisms of Resistance in Photodynamic Therapy of Cancers. Onco Targets Ther 2024; 17:605-627. [PMID: 39131905 PMCID: PMC11313505 DOI: 10.2147/ott.s457749] [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] [Received: 01/03/2024] [Accepted: 05/08/2024] [Indexed: 08/13/2024] Open
Abstract
Photodynamic therapy (PDT) is a groundbreaking approach involving the induction of cytotoxic reactive oxygen species (ROS) within tumors through visible light activation of photosensitizers (PS) in the presence of molecular oxygen. This innovative therapy has demonstrated success in treating various cancers. While PDT proves highly effective in most solid tumors, there are indications that certain cancers exhibit resistance, and some initially responsive cancers may develop intrinsic or acquired resistance to PDT. The molecular mechanisms underlying this resistance are not fully understood. Recent evidence suggests that, akin to other traditional cancer treatments, the activation of survival pathways, such as the KEAP1/Nrf2 signaling pathway, is emerging as an important mechanism of post-PDT resistance in many cancers. This article explores the dual role of Nrf2, highlighting evidence linking aberrant Nrf2 expression to treatment resistance across a range of cancers. Additionally, it delves into the specific role of Nrf2 in the context of photodynamic therapy for cancers, emphasizing evidence that suggests Nrf2-mediated upregulation of antioxidant responses and induction of drug efflux transporters are potential mechanisms of resistance to PDT in diverse cancer types. Therefore, understanding the specific role(s) of Nrf2 in PDT resistance may pave the way for the development of more effective cancer treatments using PDT.
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Affiliation(s)
| | | | | | | | | | - Bartholomew Brai
- Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria
| | | | - John Adeolu Falode
- Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria
| | - Ikenna Maximillian Odoh
- Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria
- Medical Center, Federal University, Oye-Ekiti, Ekiti-State, Nigeria
| | - Kabirat Iyabode Adegbite
- Department of Environmental Health Science, College of Basic Medical and Health Sciences, Fountain University, Osogbo, Osun State, Nigeria
| | | | - Monde Ntwasa
- Department of Life and Consumer Sciences, University of South Africa, Florida Park 1709, Roodeport, South Africa
| | - Sogolo Lucky Lebelo
- Department of Life and Consumer Sciences, University of South Africa, Florida Park 1709, Roodeport, South Africa
| | - Ademola Olabode Ayeleso
- Department of Life and Consumer Sciences, University of South Africa, Florida Park 1709, Roodeport, South Africa
- Biochemistry Programme, Bowen University, Iwo, Osun State, Nigeria
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8
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Culliford R, Lawrence SED, Mills C, Tippu Z, Chubb D, Cornish AJ, Browning L, Kinnersley B, Bentham R, Sud A, Pallikonda H, Frangou A, Gruber AJ, Litchfield K, Wedge D, Larkin J, Turajlic S, Houlston RS. Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma. Nat Commun 2024; 15:5935. [PMID: 39009593 PMCID: PMC11250826 DOI: 10.1038/s41467-024-49692-1] [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: 11/28/2023] [Accepted: 06/17/2024] [Indexed: 07/17/2024] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.
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Affiliation(s)
- Richard Culliford
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Samuel E D Lawrence
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Charlie Mills
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Zayd Tippu
- Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London, UK
- Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
- Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK
| | - Daniel Chubb
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Alex J Cornish
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Lisa Browning
- Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Ben Kinnersley
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Department of Oncology, University College London Cancer Institute, London, UK
| | - Robert Bentham
- Department of Oncology, University College London Cancer Institute, London, UK
| | - Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Husayn Pallikonda
- Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London, UK
- Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
- Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK
| | - Anna Frangou
- Nuffield Department of Medicine, Big Data Institute, University of Oxford, Oxford, UK
- Algebraic Systems Biology, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
- Algebraic Systems Biology, Centre for Systems Biology Dresden, Dresden, Germany
| | - Andreas J Gruber
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Kevin Litchfield
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - David Wedge
- Manchester Cancer Research Centre, University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester, UK
| | - James Larkin
- Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London, UK
- Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
| | - Samra Turajlic
- Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London, UK
- Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
- Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
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9
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Terlikowska KM, Dobrzycka B, Terlikowski SJ. Modifications of Nanobubble Therapy for Cancer Treatment. Int J Mol Sci 2024; 25:7292. [PMID: 39000401 PMCID: PMC11242568 DOI: 10.3390/ijms25137292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/17/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer development is related to genetic mutations in primary cells, where 5-10% of all cancers are derived from acquired genetic defects, most of which are a consequence of the environment and lifestyle. As it turns out, over half of cancer deaths are due to the generation of drug resistance. The local delivery of chemotherapeutic drugs may reduce their toxicity by increasing their therapeutic dose at targeted sites and by decreasing the plasma levels of circulating drugs. Nanobubbles have attracted much attention as an effective drug distribution system due to their non-invasiveness and targetability. This review aims to present the characteristics of nanobubble systems and their efficacy within the biomedical field with special emphasis on cancer treatment. In vivo and in vitro studies on cancer confirm nanobubbles' ability and good blood capillary perfusion; however, there is a need to define their safety and side effects in clinical trials.
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Affiliation(s)
- Katarzyna M Terlikowska
- Department of Food Biotechnology, Medical University of Bialystok, Szpitalna 37 Street, 15-295 Bialystok, Poland
| | - Bozena Dobrzycka
- Department of Gynaecology and Practical Obstetrics, Medical University of Bialystok, M. Sklodowskiej-Curie 24A Street, 15-089 Bialystok, Poland
| | - Slawomir J Terlikowski
- Department of Obstetrics, Gynaecology and Maternity Care, Medical University of Bialystok, Szpitalna 37 Street, 15-295 Bialystok, Poland
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10
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Kciuk M, Gielecińska A, Kałuzińska-Kołat Ż, Yahya EB, Kontek R. Ferroptosis and cuproptosis: Metal-dependent cell death pathways activated in response to classical chemotherapy - Significance for cancer treatment? Biochim Biophys Acta Rev Cancer 2024; 1879:189124. [PMID: 38801962 DOI: 10.1016/j.bbcan.2024.189124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 05/29/2024]
Abstract
Apoptosis has traditionally been regarded as the desired cell death pathway activated by chemotherapeutic drugs due to its controlled and non-inflammatory nature. However, recent discoveries of alternative cell death pathways have paved the way for immune-stimulatory treatment approaches in cancer. Ferroptosis (dependent on iron) and cuproptosis (dependent on copper) hold promise for selective cancer cell targeting and overcoming drug resistance. Copper ionophores and iron-bearing nano-drugs show potential for clinical therapy as single agents and as adjuvant treatments. Here we review up-to-date evidence for the involvement of metal ion-dependent cell death pathways in the cytotoxicity of classical chemotherapeutic agents (alkylating agents, topoisomerase inhibitors, antimetabolites, and mitotic spindle inhibitors) and their combinations with cuproptosis and ferroptosis inducers, indicating the prospects, advantages, and obstacles of their use.
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Affiliation(s)
- M Kciuk
- University of Lodz, Faculty of Biology and Environmental Protection, Department of Molecular Biotechnology and Genetics, Banacha St. 12/16, 90-237 Lodz, Poland.
| | - A Gielecińska
- University of Lodz, Faculty of Biology and Environmental Protection, Department of Molecular Biotechnology and Genetics, Banacha St. 12/16, 90-237 Lodz, Poland; University of Lodz, Doctoral School of Exact and Natural Sciences, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Ż Kałuzińska-Kołat
- Department of Biomedicine and Experimental Surgery, Medical University of Lodz, Narutowicza 60, 90-136 Lodz, Poland
| | - E B Yahya
- Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, Penang 11800, Malaysia
| | - R Kontek
- University of Lodz, Faculty of Biology and Environmental Protection, Department of Molecular Biotechnology and Genetics, Banacha St. 12/16, 90-237 Lodz, Poland
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11
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Baiskhanova D, Schäfer H. The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer. Antioxidants (Basel) 2024; 13:696. [PMID: 38929135 PMCID: PMC11201043 DOI: 10.3390/antiox13060696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/03/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) represents the master regulator of the cellular antioxidant response and plays a critical role in tumorigenesis. This includes a preventive effect of Nrf2 on cell death through ferroptosis, which represents an essential mechanism of therapy resistance in malignant tumors, such as pancreatic ductal adenocarcinoma (PDAC) as one of the most aggressive and still incurable tumors. Addressing this issue, we provide an overview on Nrf2 mediated antioxidant response with particular emphasis on its effect on mitochondria as the organelle responsible for the execution of ferroptosis. We further outline how deregulated Nrf2 adds to the progression and therapy resistance of PDAC, especially with respect to the role of ferroptosis in anti-cancer drug mediated cell killing and how this is impaired by Nrf2 as an essential mechanism of drug resistance. Our review further discusses recent approaches for Nrf2 inhibition by natural and synthetic compounds to overcome drug resistance based on enhanced ferroptosis. Finally, we provide an outlook on therapeutic strategies based on Nrf2 inhibition combined with ferroptosis inducing drugs.
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Affiliation(s)
- Dinara Baiskhanova
- Laboratory of Molecular Gastroenterology and Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany;
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12
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Naumann F, Kaanders J, Peeters W, Adema G, Sweep F, Bussink J, Span P. Radiotherapy induces an increase in serum antioxidant capacity reflecting tumor response. Clin Transl Radiat Oncol 2024; 45:100726. [PMID: 38292333 PMCID: PMC10825560 DOI: 10.1016/j.ctro.2024.100726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/22/2023] [Accepted: 01/10/2024] [Indexed: 02/01/2024] Open
Abstract
Background and purpose Radiotherapy (RT) is a mainstay component of treatment for patients with head and neck squamous cell carcinoma (HNSCC), but responses vary. As RT relies upon oxidative damage, antioxidant expression in response to RT-induced reactive oxygen species (ROS) could compromise treatment response. We aimed to examine local and systemic antioxidant responses to increased RT-induced ROS in relation to treatment success. Materials and methods Nuclear factor erythroid 2-related factor 2 (NRF2), the main antioxidant transcription factor, was immunofluorescently stained in FaDu cells and in tumor biopsies of patients with oral cavity/oropharynx HNSCC before and after five fractions of RT. Besides, total antioxidant capacity (TAC) was analyzed in HNSCC tumor cells in vitro and in serum of HNSCC patients before, during, and after RT. Results Data revealed an increase in NRF2 expression and TAC in head and neck cancer cells in vitro over the course of 5 daily fractions of 2 Gy. In accordance, also in patients' tumors NRF2 expression increased, which was associated with increased serum TAC during RT. Increasing serum TAC was related to impaired local tumor control. Conclusion Radiation induced NRF2 expression and upregulated TAC, which may compromise the effect of RT-induced ROS. Changes in serum TAC during RT could serve as a novel predictor of treatment outcome in HNSCC patients.Medical Ethics Review Committee (CMO) approval - CMO number: 2007/104.
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Affiliation(s)
- F.V. Naumann
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - J.H.A.M. Kaanders
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - W.J.M. Peeters
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - G.J. Adema
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - F.C.G.J. Sweep
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - J. Bussink
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - P.N. Span
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
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13
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Sun B, Zhang L, Wu B, Luo X. A Morpholine Derivative N-(4-Morpholinomethylene)ethanesulfonamide Induces Ferroptosis in Tumor Cells by Targeting NRF2. Biol Pharm Bull 2024; 47:417-426. [PMID: 38296488 DOI: 10.1248/bpb.b23-00544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
Small molecule drugs containing morpholine-based moieties have become crucial candidates in the tumor targeted therapy strategies, but the specific molecular mechanisms of these drugs causing tumor cell death require further investigation. The morpholine derivative N-(4-morpholinomethylene)ethanesulfonamide (MESA) was used to stimulate prostate and ovarian cancer cells and we focused on the ferroptosis effects, including the target molecule and signal pathways mediated by MESA. The results showed that MESA could induce ferroptosis to cause the proliferation inhibition and apoptosis effects of tumor cells according to the identification of ferroptosis inhibitor fer-1 and other cell death inhibitors. Further MESA could significantly increase the intracellular malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+ levels in tumor cells and mediate the dynamic changes of ferroptosis-relative molecules GPX4, nuclear factor erythroid2-related factor 2 (NRF2), ACSL4, SLC7A11 and P62-Kelch-like ECH-associated protein 1 (KEAP1)-NRF2-antioxidant response element (ARE) signal pathways. Further, NRF2 overexpression could reduce the tumor cell death and ROS levels exposure to MESA. Most importantly, it was confirmed that MESA could bind to NRF2 protein through molecular docking and thermal stability assays and NRF2 was a target molecule of MESA for inducing ferroptosis effects in tumor cells. Collectively, our findings indicated the ferroptosis effects of the morpholine derivative MESA in prostate and ovarian cancer cells and its function mechanism including targeted molecule and signal pathways, which would be helpful for developing MESA as a prospective small molecule drug for cancer therapy based on cell ferroptosis.
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Affiliation(s)
| | | | - Binhua Wu
- Department of Obstetrics and Gynecology of Affiliated Hospital, the Marine Biomedical Research Institute, Guangdong Medical University
| | - Xiping Luo
- First Affiliated Hospital of Jinan University
- Department of Gynecology, Guangdong Women and Children Hospital
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14
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Yu W, Zhang F, Meng D, Zhang X, Feng Y, Yin G, Liang P, Chen S, Liu H. Mechanism of Action and Related Natural Regulators of Nrf2 in Nonalcoholic Fatty Liver Disease. Curr Drug Deliv 2024; 21:1300-1319. [PMID: 39034715 DOI: 10.2174/0115672018260113231023064614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/19/2023] [Accepted: 09/01/2023] [Indexed: 07/23/2024]
Abstract
With the acceleration of people's pace of life, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world, which greatly threatens people's health and safety. Therefore, there is still an urgent need for higher-quality research and treatment in this area. Nuclear factor Red-2-related factor 2 (Nrf2), as a key transcription factor in the regulation of oxidative stress, plays an important role in inducing the body's antioxidant response. Although there are no approved drugs targeting Nrf2 to treat NAFLD so far, it is still of great significance to target Nrf2 to alleviate NAFLD. In recent years, studies have reported that many natural products treat NAFLD by acting on Nrf2 or Nrf2 pathways. This article reviews the role of Nrf2 in the pathogenesis of NAFLD and summarizes the currently reported natural products targeting Nrf2 or Nrf2 pathway for the treatment of NAFLD, which provides new ideas for the development of new NAFLD-related drugs.
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Affiliation(s)
- Wenfei Yu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Fengxia Zhang
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People's Republic of China
| | - Decheng Meng
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Xin Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Yanan Feng
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Guoliang Yin
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Pengpeng Liang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Suwen Chen
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Hongshuai Liu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
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15
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Houlston R, Culliford R, Lawrence S, Mills C, Tippu Z, Chubb D, Cornish A, Browining L, Kinnersley B, Bentham R, Sud A, Pallikonda H, Frangou A, Gruber A, Litchfield K, Wedge D, Larkin J, Turajlic S. Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma. RESEARCH SQUARE 2023:rs.3.rs-3675752. [PMID: 38106039 PMCID: PMC10723546 DOI: 10.21203/rs.3.rs-3675752/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing the most detailed somatic mutational landscape to date. We identify new driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for drug repurposing. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The twin observations that higher T-cell infiltration is associated with better outcome and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Amit Sud
- The Institute of Cancer Research
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16
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Pandey A, Trigun SK. Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2). J Cell Biochem 2023; 124:1289-1308. [PMID: 37450699 DOI: 10.1002/jcb.30447] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
Modulation of autophagy is evolving as a relevant strategy in cancer pathogenesis and therapeutic intervention and hence, needs to be examined as a target for the promising anticancer agents. Fisetin, a dietary flavanol, is emerging as a potent anticancer agent, however, its tumour-specific pharmacological targets remain largely unexplored. This article describes correlative profiles of autophagy and apoptotic markers versus nuclear factor erythroid 2-related factor 2 (Nrf2) and reactive oxygen species (ROS) in the colorectal cancer (CRC) cell line SW-480. As compared to the untreated cells, significantly less number of fluorescent detected autophagic vacuoles (AVOs) in the fisetin-treated cells coincided with a similar decline of the autophagy flux markers, Beclin 1 and microtubule-associated protein-1 light chain-3 and accumulation of p62 in those cells. The significantly increased number of annexin-V/propidium iodide (+/+) positive and acridine orange/ethidium bromide-stained apoptotic cells coincided with the enhanced signals for the cleaved caspase 3 and nuclear PARP-1 in those fisetin-treated cells. This was consistent with the collapse of mitochondrial membrane potential and release of cytochrome c. The fisetin-treated cells showed increased ROS level and a significant decline in nuclear Nrf2 immunosignal versus recovery in nuclear Nrf2 due to the treatment with curcumin and resveratrol (Nrf2 activators) and thus, suggesting a role of Nrf2 suppression in fisetin-mediated apoptosis in SW-480 cells. The effect of chloroquine, an autophagy inhibitor, resulted into declined number of AVOs and enhanced apoptosis, similar to that of the fisetin effect. Also, regaining of AVOs number and reduced apoptosis of CRC cells due to the treatment with rapamycin, an autophagy inducer, could be observed. These loss and gain of functions experiments thus suggested a correlation between fisetin-mediated autophagy suppression and apoptotic induction in a colorectal cell line.
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Affiliation(s)
- Akanksha Pandey
- Department of Zoology, Biochemistry Section, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Surendra Kumar Trigun
- Department of Zoology, Biochemistry Section, Institute of Science, Banaras Hindu University, Varanasi, India
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17
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Huang Y, Yang W, Yang L, Wang T, Li C, Yu J, Zhang P, Yin Y, Li R, Tao K. Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis. Sci Rep 2023; 13:14359. [PMID: 37658132 PMCID: PMC10474100 DOI: 10.1038/s41598-023-41490-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 08/28/2023] [Indexed: 09/03/2023] Open
Abstract
Oxaliplatin is widely used in chemotherapy for colorectal cancer (CRC), but its sensitivity has become a major obstacle to limiting efficacy. Many literatures reported that Nrf2 activation promoted tumor chemoresistance. In this study, we explored the role and mechanism of Nrf2 inhibition in oxaliplatin-based chemosensitivity of CRC. In vitro experiments, we applied 4-octyl itaconate (4-OI) to activate Nrf2, and used lentivirus to knock down Nrf2 in CRC cell lines. By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. 4-OI, an Nrf2 activator, reduced the sensibility of CRC cells to oxaliplatin and lobaplatin, while the knockdown of Nrf2 promoted the sensibility of CRC cells to oxaliplatin and lobaplatin. Through the public databases, we found that the expression of GPX4 in normal tissues was lower compared with cancer tissues in CRC, and the high GPX4 expression predicted a poor prognosis. Meanwhile, we found that oxaliplatin reduced the expression of GPX4 in vitro. The knockdown of Nrf2 enhanced the effects of oxaliplatin to reduce the expression of GPX4 and GSH content, and increase the MDA content, which enhanced oxaliplatin-induced ferroptosis. Subsequently, we found that oxaliplatin promoted the expression of GSDME-N, and induced LDH, IL-1β, and TNF-a release, and the knockdown of Nrf2 aggravated the occurrence of GSMDE-mediated pyroptosis. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.
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Affiliation(s)
- Yongzhou Huang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
- Department of General Surgery, First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, 832008, People's Republic of China
| | - Wenchang Yang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Lei Yang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Tao Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Chengguo Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Jiaxian Yu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Yuping Yin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China
| | - Ruidong Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China.
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, People's Republic of China.
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18
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Zhou X, An B, Lin Y, Ni Y, Zhao X, Liang X. Molecular mechanisms of ROS-modulated cancer chemoresistance and therapeutic strategies. Biomed Pharmacother 2023; 165:115036. [PMID: 37354814 DOI: 10.1016/j.biopha.2023.115036] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/12/2023] [Accepted: 06/20/2023] [Indexed: 06/26/2023] Open
Abstract
Drug resistance is the main obstacle to achieving a cure in many cancer patients. Reactive oxygen species (ROS) are master regulators of cancer development that act through complex mechanisms. Remarkably, ROS levels and antioxidant content are typically higher in drug-resistant cancer cells than in non-resistant and normal cells, and have been shown to play a central role in modulating drug resistance. Therefore, determining the underlying functions of ROS in the modulation of drug resistance will contribute to develop therapies that sensitize cancer resistant cells by leveraging ROS modulation. In this review, we summarize the notable literature on the sources and regulation of ROS production and highlight the complex roles of ROS in cancer chemoresistance, encompassing transcription factor-mediated chemoresistance, maintenance of cancer stem cells, and their impact on the tumor microenvironment. We also discuss the potential of ROS-targeted therapies in overcoming tumor therapeutic resistance.
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Affiliation(s)
- Xiaoting Zhou
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, PR China
| | - Biao An
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, PR China
| | - Yi Lin
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, PR China
| | - Yanghong Ni
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, PR China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, PR China
| | - Xiao Liang
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, PR China.
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19
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Gao X, Wang B, Huang Y, Wu M, Li Y, Li Y, Zhu X, Wu M. Role of the Nrf2 Signaling Pathway in Ovarian Aging: Potential Mechanism and Protective Strategies. Int J Mol Sci 2023; 24:13327. [PMID: 37686132 PMCID: PMC10488162 DOI: 10.3390/ijms241713327] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
The ovary holds a significant role as a reproductive endocrine organ in women, and its aging process bears implications such as menopause, decreased fertility, and long-term health risks including osteoporosis, cardiovascular disorders, and cognitive decline. The phenomenon of oxidative stress is tightly linked to the aging metabolic processes. More and more studies have demonstrated that oxidative stress impacts both physiologic and pathologic ovarian aging, and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating the antioxidant response. Furthermore, various therapeutic approaches have been identified to ameliorate ovarian aging by modulating the Nrf2 pathway. This review summarizes the important role of the Nrf2/ Kelch-like ECH-associated protein 1 (Keap1) signaling pathway in regulating oxidative stress and influencing ovarian aging. Additionally, it highlights the therapeutic strategies aimed at targeting the Nrf2/Keap1 pathway.
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Affiliation(s)
- Xiaofan Gao
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
| | - Bo Wang
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
| | - Yibao Huang
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
| | - Meng Wu
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
| | - Yuting Li
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
| | - Yinuo Li
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
| | - Xiaoran Zhu
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
| | - Mingfu Wu
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (X.G.); (B.W.); (Y.H.); (M.W.); (Y.L.); (Y.L.); (X.Z.)
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan 430030, China
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20
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Zhang Z, Chen L, Zhao C, Gong Q, Tang Z, Li H, Tao J. CASC9 potentiates gemcitabine resistance in pancreatic cancer by reciprocally activating NRF2 and the NF-κB signaling pathway. Cell Biol Toxicol 2023; 39:1549-1560. [PMID: 35913601 DOI: 10.1007/s10565-022-09746-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 07/06/2022] [Indexed: 11/02/2022]
Abstract
Gemcitabine resistance is a frequently occurring and intractable obstacle in pancreatic cancer treatment. However, the underlying mechanisms require further investigation. Adaptive regulation of oxidative stress and aberrant activation of the NF-κB signaling pathway are associated with resistance to chemotherapy. Here, we found that gemcitabine upregulated the expression of CASC9 in a dose-dependent manner, partially via induction of reactive oxygen species, whereas inhibition of CASC9 expression enhanced gemcitabine-induced oxidative stress and apoptosis in pancreatic cancer cells. Furthermore, suppression of CASC9 level inhibited the expression of NRF2 and the downstream genes NQO1 and HO-1, and vice versa, indicating that CASC9 forms a positive feedback loop with NRF2 signaling and modulates the level of oxidative stress. Silencing CASC9 attenuated NF-κB pathway activation in pancreatic cancer cells and synergistically enhanced the cytotoxic effect of gemcitabine chemotherapy in vivo. In conclusion, our findings suggest that CASC9 plays a key role in driving resistance to gemcitabine through a reciprocal loop with the NRF2-antioxidant signaling pathway and by activating NF-κB signaling. Our study reveals potential targets that can effectively reverse resistance to gemcitabine chemotherapy.
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Affiliation(s)
- Zhengle Zhang
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China
| | - Longjiang Chen
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China
| | - Chuanbing Zhao
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China
| | - Qiong Gong
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China
| | - Zhigang Tang
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China
| | - Hanjun Li
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China.
| | - Jing Tao
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China.
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21
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Fuertes-Agudo M, Luque-Tévar M, Cucarella C, Martín-Sanz P, Casado M. Advances in Understanding the Role of NRF2 in Liver Pathophysiology and Its Relationship with Hepatic-Specific Cyclooxygenase-2 Expression. Antioxidants (Basel) 2023; 12:1491. [PMID: 37627486 PMCID: PMC10451723 DOI: 10.3390/antiox12081491] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
Oxidative stress and inflammation play an important role in the pathophysiological changes of liver diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes, thus playing a key role in protecting against oxidative damage. Cyclooxygenase-2 (COX-2) is a key enzyme in prostaglandin biosynthesis. Its expression has always been associated with the induction of inflammation, but we have shown that, in addition to possessing other benefits, the constitutive expression of COX-2 in hepatocytes is beneficial in reducing inflammation and oxidative stress in multiple liver diseases. In this review, we summarized the role of NRF2 as a main agent in the resolution of oxidative stress, the crucial role of NRF2 signaling pathways during the development of chronic liver diseases, and, finally we related its action to that of COX-2, where it appears to operate as its partner in providing a hepatoprotective effect.
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Affiliation(s)
- Marina Fuertes-Agudo
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - María Luque-Tévar
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Carme Cucarella
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Paloma Martín-Sanz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
- Instituto de Investigaciones Biomédicas (IIB) “Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | - Marta Casado
- Instituto de Biomedicina de Valencia (IBV), CSIC, Jaume Roig 11, 46010 Valencia, Spain; (M.F.-A.); (M.L.-T.); (C.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
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22
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Mukherjee AG, Gopalakrishnan AV. The mechanistic insights of the antioxidant Keap1-Nrf2 pathway in oncogenesis: a deadly scenario. Med Oncol 2023; 40:248. [PMID: 37480500 DOI: 10.1007/s12032-023-02124-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/06/2023] [Indexed: 07/24/2023]
Abstract
The Nuclear factor erythroid 2-related factor 2 (Nrf2) protein has garnered significant interest due to its crucial function in safeguarding cells and tissues. The Nrf2 protein is crucial in preserving tissue integrity by safeguarding cells against metabolic, xenobiotic and oxidative stress. Due to its various functions, Nrf2 is a potential pharmacological target for reducing the incidence of diseases such as cancer. However, mutations in Keap1-Nrf2 are not consistently favored in all types of cancer. Instead, they seem to interact with specific driver mutations of tumors and their respective tissue origins. The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway mutations are a powerful cancer adaptation that utilizes inherent cytoprotective pathways, encompassing nutrient metabolism and ROS regulation. The augmentation of Nrf2 activity elicits significant alterations in the characteristics of neoplastic cells, such as resistance to radiotherapy and chemotherapy, safeguarding against apoptosis, heightened invasiveness, hindered senescence, impaired autophagy and increased angiogenesis. The altered activity of Nrf2 can arise from diverse genetic and epigenetic modifications that instantly impact Nrf2 regulation. The present study aims to showcase the correlation between the Keap1-Nrf2 pathway and the progression of cancers, emphasizing genetic mutations, metabolic processes, immune regulation, and potential therapeutic strategies. This article delves into the intricacies of Nrf2 pathway anomalies in cancer, the potential ramifications of uncontrolled Nrf2 activity, and therapeutic interventions to modulate the Keap1-Nrf2 pathway.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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23
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Haji N, Faizi M, Koutentis PA, Carty MP, Aldabbagh F. Heterocyclic Iminoquinones and Quinones from the National Cancer Institute (NCI, USA) COMPARE Analysis. Molecules 2023; 28:5202. [PMID: 37446864 DOI: 10.3390/molecules28135202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/21/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition patterns across the 60-cell line panel of the NCI Developmental Therapeutics Program (DTP). Many natural products and synthetic analogues are revealed as potential NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates, through correlations to dipyridoimidazo[5,4-f]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors, through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of the active compound with benzo[e]perimidines, phenoxazinones, benz[f]pyrido[1,2-a]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-b]naphthoquinones, hypothesised as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-b][1,4]oxazepane-6,11-diones, benzo[a]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanaomycin A, and analogues of griseusin A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidising moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.
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Affiliation(s)
- Naemah Haji
- Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, London KT1 2EE, UK
| | - Masoma Faizi
- Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, London KT1 2EE, UK
| | | | - Michael P Carty
- School of Biological and Chemical Sciences, University of Galway, University Road, H91 TK33 Galway, Ireland
| | - Fawaz Aldabbagh
- Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, London KT1 2EE, UK
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24
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Lee H, Min SK, Cho MS, Lee HK. Impact of Nrf2 overexpression on cholangiocarcinoma treatment and clinical prognosis. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2023; 19:18-26. [PMID: 37449395 DOI: 10.14216/kjco.23004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
PURPOSE Nrf2 regulates antioxidant protein expression and protects against drug toxicity and oxidative stress, whereas Keap1 controls Nrf2 activity. The Keap1-Nrf2 pathway affects the prognosis of various cancers, however, its effect on cholangiocarcinoma chemoresistance and prognosis remains unclear. This study aimed to determine whether the Keap1-Nrf2 pathway affects chemoresistance and prognosis of distal cholangiocarcinoma. METHODS We investigated the correlation between Nrf2 and Keap1 expression and clinical characteristics and prognosis in 91 patients with distal cholangiocarcinoma who underwent curative surgery. Immunohistochemical staining was performed on paraffin blocks using primary antibodies against Nrf2 and Keap1. The relationship between Keap1 and Nrf2 protein expression levels, and clinical characteristics and prognosis was examined. RESULTS Nrf2 expression was not associated with overall survival in patients who did not receive adjuvant chemotherapy (P=0.994). Among patients receiving adjuvant chemotherapy, the Nrf2 low expression group had a significantly longer median overall survival than the Nrf2 high expression group in Kaplan-Meier survival analysis (P=0.019). In multivariate analysis, high expression of Nrf2 was confirmed as an independent poor prognostic factor in the group receiving adjuvant chemotherapy (P=0.041). CONCLUSION This study suggests that Nrf2 overexpression reduces the efficacy of adjuvant chemotherapy in distal cholangiocarcinoma.
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Affiliation(s)
- Huisong Lee
- Department of Surgery, Ewha Womans University College of Medicine, Seoul, Korea
| | - Seog Ki Min
- Department of Surgery, Ewha Womans University College of Medicine, Seoul, Korea
| | - Min-Sun Cho
- Department of Pathology, Ewha Womans University College of Medicine, Seoul, Korea
| | - Hyeon Kook Lee
- Department of Surgery, Ewha Womans University College of Medicine, Seoul, Korea
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25
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Modi R, McKee N, Zhang N, Alwali A, Nelson S, Lohar A, Ostafe R, Zhang DD, Parkinson EI. Stapled Peptides as Direct Inhibitors of Nrf2-sMAF Transcription Factors. J Med Chem 2023; 66:6184-6192. [PMID: 37097833 PMCID: PMC10184664 DOI: 10.1021/acs.jmedchem.2c02037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Indexed: 04/26/2023]
Abstract
Nuclear factor erythroid-related 2-factor 2 (Nrf2) is a transcription factor traditionally thought of as a cellular protector. However, in many cancers, Nrf2 is constitutively activated and correlated with therapeutic resistance. Nrf2 heterodimerizes with small musculoaponeurotic fibrosarcoma Maf (sMAF) transcription factors, allowing binding to the antioxidant responsive element (ARE) and induction of transcription of Nrf2 target genes. While transcription factors are historically challenging to target, stapled peptides have shown great promise for inhibiting these protein-protein interactions. Herein, we describe the first direct cell-permeable inhibitor of Nrf2/sMAF heterodimerization. N1S is a stapled peptide designed based on AlphaFold predictions of the interactions between Nrf2 and sMAF MafG. A cell-based reporter assay combined with in vitro biophysical assays demonstrates that N1S directly inhibits Nrf2/MafG heterodimerization. N1S treatment decreases the transcription of Nrf2-dependent genes and sensitizes Nrf2-dependent cancer cells to cisplatin. Overall, N1S is a promising lead for the sensitization of Nrf2-addicted cancers.
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Affiliation(s)
- Ramya Modi
- Department
of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
| | - Nick McKee
- Department
of Pharmacology and Toxicology, University
of Arizona, Tucson, Arizona 85721, United States
| | - Ning Zhang
- Department
of Pharmacology and Toxicology, University
of Arizona, Tucson, Arizona 85721, United States
| | - Amir Alwali
- Department
of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
| | - Samantha Nelson
- Department
of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
| | - Aditi Lohar
- Department
of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
| | - Raluca Ostafe
- Molecular
Evolution Protein Engineering and Production, Purdue University, West Lafayette, Indiana 47907, United States
| | - Donna D. Zhang
- Department
of Pharmacology and Toxicology, University
of Arizona, Tucson, Arizona 85721, United States
| | - Elizabeth I. Parkinson
- Department
of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
- Department
of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States
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26
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He X, Zhou Y, Chen W, Zhao X, Duan L, Zhou H, Li M, Yu Y, Zhao J, Guo Y, Gu H, Jiang Y, Dong Z, Liu K. Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma. Oncogene 2023; 42:1209-1223. [PMID: 36841865 DOI: 10.1038/s41388-023-02636-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/12/2023] [Accepted: 02/14/2023] [Indexed: 02/27/2023]
Abstract
Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients' overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.
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Affiliation(s)
- Xinyu He
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China
| | - Yubing Zhou
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China
| | - Wenjing Chen
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China
| | - Xiaokun Zhao
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China
| | - Lina Duan
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China
| | - Hao Zhou
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Mingzhu Li
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China
| | - Yin Yu
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China
| | - Jimin Zhao
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China.,Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.,Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China
| | - Yaping Guo
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Huihui Gu
- Basic Medicine Sciences Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Yanan Jiang
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. .,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. .,Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.
| | - Zigang Dong
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. .,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. .,Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China.
| | - Kangdong Liu
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. .,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. .,Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China. .,Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China. .,Basic Medicine Sciences Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.
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27
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Watanabe E, Yokoi A, Yoshida K, Sugiyama M, Kitagawa M, Nishino K, Yamamoto E, Niimi K, Yamamoto Y, Kajiyama H. Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma. Cancer Med 2023; 12:4543-4556. [PMID: 36106577 PMCID: PMC9972027 DOI: 10.1002/cam4.5243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/20/2022] [Accepted: 08/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy. METHODS Three choriocarcinoma cell lines (JAR, JEG-3, and BeWo) and a human extravillous trophoblast cell line (HTR-8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA-approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor-bearing mice. Functional analyses of drug effects were performed based on RNA sequencing. RESULTS Muti-step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti-cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis-related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell-bearing mice model. CONCLUSION Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T-cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis-related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma.
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Affiliation(s)
- Eri Watanabe
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Yokoi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Institute for Advanced Research, Nagoya University, Nagoya, Japan
| | - Kosuke Yoshida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Institute for Advanced Research, Nagoya University, Nagoya, Japan
| | - Mai Sugiyama
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masami Kitagawa
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kimihiro Nishino
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Eiko Yamamoto
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kaoru Niimi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Yamamoto
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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León-Letelier RA, Abdel Sater AH, Chen Y, Park S, Wu R, Irajizad E, Dennison JB, Katayama H, Vykoukal JV, Hanash S, Ostrin EJ, Fahrmann JF. Kynureninase Upregulation Is a Prominent Feature of NFR2-Activated Cancers and Is Associated with Tumor Immunosuppression and Poor Prognosis. Cancers (Basel) 2023; 15:cancers15030834. [PMID: 36765792 PMCID: PMC9913753 DOI: 10.3390/cancers15030834] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023] Open
Abstract
The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is frequently activated in various cancer types. Aberrant activation of NRF2 in cancer is attributed to gain-of-function mutations in the NRF2-encoding gene NFE2L2 or a loss of function of its suppressor, Kelch-like ECH-associated protein 1 (KEAP1). NRF2 activation exerts pro-tumoral effects in part by altering cancer cell metabolism. Previously, we reported a novel mechanism of NRF2 tumoral immune suppression through the selective upregulation of the tryptophan-metabolizing enzyme kynureninase (KYNU) in lung adenocarcinoma. In the current study, we explored the relevance of NRF2-mediated KYNU upregulation across multiple cancer types. Specifically, using a gene expression dataset for 9801 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), we demonstrated that elevated KYNU parallels increased gene-based signatures of NRF2-activation and that elevated tumoral KYNU mRNA expression is strongly associated with an immunosuppressive tumor microenvironment, marked by high expression of gene-based signatures of Tregs as well as the immune checkpoint blockade-related genes CD274 (PDL-1), PDCD1 (PD-1), and CTLA4, regardless of the cancer type. Cox proportional hazard models further revealed that increased tumoral KYNU gene expression was prognostic for poor overall survival in several cancer types, including thymoma, acute myeloid leukemia, low-grade glioma, kidney renal papillary cell carcinoma, stomach adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC). Using PDAC as a model system, we confirmed that siRNA-mediated knockdown of NRF2 reduced KYNU mRNA expression, whereas activation of NFE2L2 (the coding gene for NRF2) through either small-molecule agonists or siRNA-mediated knockdown of KEAP1 upregulated KYNU in PDAC cells. Metabolomic analyses of the conditioned medium from PDAC cell lines revealed elevated levels of KYNU-derived anthranilate, confirming that KYNU was enzymatically functional. Collectively, our study highlights the activation of the NRF2-KYNU axis as a multi-cancer phenomenon and supports the relevance of tumoral KYNU as a marker of tumor immunosuppression and as a prognostic marker for poor overall survival.
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Affiliation(s)
- Ricardo A. León-Letelier
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ali H. Abdel Sater
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yihui Chen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Soyoung Park
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ranran Wu
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ehsan Irajizad
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jennifer B. Dennison
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hiroyuki Katayama
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jody V. Vykoukal
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Samir Hanash
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Edwin J. Ostrin
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (E.J.O.); (J.F.F.)
| | - Johannes F. Fahrmann
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (E.J.O.); (J.F.F.)
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Effects of Antioxidant Gene Overexpression on Stress Resistance and Malignization In Vitro and In Vivo: A Review. Antioxidants (Basel) 2022; 11:antiox11122316. [PMID: 36552527 PMCID: PMC9774954 DOI: 10.3390/antiox11122316] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/17/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Reactive oxygen species (ROS) are normal products of a number of biochemical reactions and are important signaling molecules. However, at the same time, they are toxic to cells and have to be strictly regulated by their antioxidant systems. The etiology and pathogenesis of many diseases are associated with increased ROS levels, and many external stress factors directly or indirectly cause oxidative stress in cells. Within this context, the overexpression of genes encoding the proteins in antioxidant systems seems to have become a viable approach to decrease the oxidative stress caused by pathological conditions and to increase cellular stress resistance. However, such manipulations unavoidably lead to side effects, the most dangerous of which is an increased probability of healthy tissue malignization or increased tumor aggression. The aims of the present review were to collect and systematize the results of studies devoted to the effects resulting from the overexpression of antioxidant system genes on stress resistance and carcinogenesis in vitro and in vivo. In most cases, the overexpression of these genes was shown to increase cell and organism resistances to factors that induce oxidative and genotoxic stress but to also have different effects on cancer initiation and promotion. The last fact greatly limits perspectives of such manipulations in practice. The overexpression of GPX3 and SOD3 encoding secreted proteins seems to be the "safest" among the genes that can increase cell resistance to oxidative stress. High efficiency and safety potential can also be found for SOD2 overexpression in combinations with GPX1 or CAT and for similar combinations that lead to no significant changes in H2O2 levels. Accumulation, systematization, and the integral analysis of data on antioxidant gene overexpression effects can help to develop approaches for practical uses in biomedical and agricultural areas. Additionally, a number of factors such as genetic and functional context, cell and tissue type, differences in the function of transcripts of one and the same gene, regulatory interactions, and additional functions should be taken into account.
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Kryszczuk M, Kowalczuk O. Significance of NRF2 in physiological and pathological conditions an comprehensive review. Arch Biochem Biophys 2022; 730:109417. [DOI: 10.1016/j.abb.2022.109417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/22/2022] [Accepted: 09/24/2022] [Indexed: 11/30/2022]
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Yang PW, Xu PL, Cheng CS, Jiao JY, Wu Y, Dong S, Xie J, Zhu XY. Integrating network pharmacology and experimental models to investigate the efficacy of QYHJ on pancreatic cancer. JOURNAL OF ETHNOPHARMACOLOGY 2022; 297:115516. [PMID: 35817247 DOI: 10.1016/j.jep.2022.115516] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 06/19/2022] [Accepted: 06/26/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Qingyihuaji decoction (QYHJ) is composed of seven herbs: Scutellaria barbata D.Don (Banzhilian, HSB), Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan, GP), Oldenlandia diffusa (Willd.) Roxb. (Baihuasheshecao, HDH), Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi, GL), Myristica fragrans Houtt. (Doukou, AK), and Amorphophallus kiusianus (Makino) Makino (Sheliugu, RA), and Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf (Yiyiren, CL). QYHJ has been reported to exhibit clinical efficacy in the treatment of pancreatic adenocarcinoma (PAAD). However, the molecular mechanism remains unclear. AIM OF THE STUDY This study explores the therapeutic mechanism of QYHJ in the treatment of PAAD using network pharmacology to identify related targets and pathways in vivo and in vitro. MATERIALS AND METHODS The bioactive compounds of QYHJ were retrieved and screened using the ADME network pharmacology approach, followed by compound-target prediction and overlapping genes between PAAD oncogenes and QYHJ target genes. The compound-target-pathway network was established using The KEGG pathway, GO analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis to identify potential action pathways. The effects of QYHJ on PAAD were evaluated in vivo and in vitro, and the predicted targets and potential pathways related to QYHJ in PAAD treatment were evaluated using qRT-PCR and immunoblotting. RESULTS A total of 68 bioactive compounds of QYHJ fulfilled the ADME screening criterion, and their respective 242 target genes were retrieved. The compound-target-disease network identified 11 possible target genes. The KEGG pathway analysis showed significant enrichment of pathways in cancers, involving regulating cancer-related pathways of inflammation, oxidative stress, and apoptosis. Furthermore, QYHJ inhibited PAAD growth in vivo; suppressed cell proliferation, invasion, and migration of PAAD; and induced cellular apoptosis in vitro. The qRT-PCR results showed that QYHJ suppressed the mRNA expression of ICAM1, VCAM1, and Bcl2, and increased that of HMOX1 and NQO1. Immunoblotting revealed changes in the PI3K/AKT/mTOR, Keap1/Nrf2/HO-1/NQO1, and Bcl2/Bax pathways upon QYHJ treatment. CONCLUSIONS QYHJ can suppress PAAD growth and progression through various mechanisms, including anti-inflammation and apoptosis-induction.
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Affiliation(s)
- Pei-Wen Yang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Pan-Ling Xu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, Anhui, China
| | - Chien-Shan Cheng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China; Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, 200025, Shanghai, China
| | - Ju-Ying Jiao
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, 200025, Shanghai, China
| | - Shu Dong
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Jing Xie
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
| | - Xiao-Yan Zhu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
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Chu X, Zhong L, Dan W, Wang X, Zhang Z, Liu Z, Lu Y, Shao X, Zhou Z, Chen S, Liu B. DNMT3A R882H mutation drives daunorubicin resistance in acute myeloid leukemia via regulating NRF2/NQO1 pathway. Cell Commun Signal 2022; 20:168. [PMID: 36303144 PMCID: PMC9615155 DOI: 10.1186/s12964-022-00978-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/24/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND DNA methyltransferase 3A (DNMT3A) often mutate on arginine 882 (DNMT3AR882) in acute myeloid leukemia (AML). AML patients with DNMT3A R882 mutation are usually resistant to daunorubicin treatment; however, the associated mechanism is still unclear. Therefore, it is urgent to investigate daunorubicin resistance in AML patients with DNMT3A R882 mutant. METHOD AML cell lines with DNMT3A-wild type (DNMT3A-WT), and DNMT3A-Arg882His (DNMT3A-R882H) mutation were constructed to investigate the role of DNMT3A R882H mutation on cell proliferation, apoptosis and cells' sensitivity to Danunorubin. Bioinformatics was used to analyze the role of nuclear factor-E2-related factor (NRF2) in AML patients with DNMT3A R882 mutation. The regulatory mechanism of DNMT3A R882H mutation on NRF2 was studied by Bisulfite Sequencing and CO-IP. NRF2 inhibitor Brusatol (Bru) was used to explore the role of NRF2 in AML cells carried DNMT3A R882H mutation. RESULTS AML cells with a DNMT3A R882H mutation showed high proliferative and anti-apoptotic activities. In addition, mutant cells were less sensitive to daunorubicin and had a higher NRF2 expression compared with those in WT cells. Furthermore, the NRF2/NQO1 pathway was activated in mutant cells in response to daunorubicin treatment. DNMT3A R882H mutation regulated the expression of NRF2 via influencing protein stability rather than decreasing methylation of NRF2 promoter. Also, NRF2/NQO1 pathway inhibition improved mutant cells' sensitivity to daunorubicin significantly. CONCLUSION Our findings identified NRF2 as an important player in the regulation of cell apoptosis through which helps mediate chemoresistance to daunorubicin in AML cells with DNMT3A R882H mutation. Targeting NRF2 might be a novel therapeutic approach to treat AML patients with a DNMT3A R882H mutation. Video abstract.
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Affiliation(s)
- Xuan Chu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Liang Zhong
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Wenran Dan
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Xiao Wang
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Zhonghui Zhang
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Zhenyan Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Yang Lu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Xin Shao
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Ziwei Zhou
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Shuyu Chen
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China
| | - Beizhong Liu
- Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing, 402160, China. .,Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
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Nrf2 Modulation in Breast Cancer. Biomedicines 2022; 10:biomedicines10102668. [PMID: 36289931 PMCID: PMC9599257 DOI: 10.3390/biomedicines10102668] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/05/2022] [Accepted: 10/19/2022] [Indexed: 12/05/2022] Open
Abstract
Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents.
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Sapochnik D, Raimondi AR, Medina V, Naipauer J, Mesri EA, Coso O. A major role for Nrf2 transcription factors in cell transformation by KSHV encoded oncogenes. Front Oncol 2022; 12:890825. [PMID: 36212441 PMCID: PMC9534600 DOI: 10.3389/fonc.2022.890825] [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] [Received: 03/06/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Kaposi's sarcoma (KS) is the most common tumor in AIDS patients. The highly vascularized patient's skin lesions are composed of cells derived from the endothelial tissue transformed by the KSHV virus. Heme oxygenase-1 (HO-1) is an enzyme upregulated by the Kaposi´s sarcoma-associated herpesvirus (KSHV) and highly expressed in human Kaposi Sarcoma (KS) lesions. The oncogenic G protein-coupled receptor (KSHV-GPCR or vGPCR) is expressed by the viral genome in infected cells. It is involved in KS development, HO-1 expression, and vascular endothelial growth factor (VEGF) expression. vGPCR induces HO-1 expression and HO-1 dependent transformation through the Ga13 subunit of heterotrimeric G proteins and the small GTPase RhoA. We have found several lines of evidence supporting a role for Nrf2 transcription factors and family members in the vGPCR-Ga13-RhoA signaling pathway that converges on the HO-1 gene promoter. Our current information assigns a major role to ERK1/2MAPK pathways as intermediates in signaling from vGPCR to Nrf2, influencing Nrf2 translocation to the cell nucleus, Nrf2 transactivation activity, and consequently HO-1 expression. Experiments in nude mice show that the tumorigenic effect of vGPCR is dependent on Nrf2. In the context of a complete KSHV genome, we show that the lack of vGPCR increased cytoplasmic localization of Nrf2 correlated with a downregulation of HO-1 expression. Moreover, we also found an increase in phospho-Nrf2 nuclear localization in mouse KS-like KSHV (positive) tumors compared to KSHV (negative) mouse KS-like tumors. Our data highlights the fundamental role of Nrf2 linking vGPCR signaling to the HO-1 promoter, acting upon not only HO-1 gene expression regulation but also in the tumorigenesis induced by vGPCR. Overall, these data pinpoint this transcription factor or its associated proteins as putative pharmacological or therapeutic targets in KS.
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Affiliation(s)
- Daiana Sapochnik
- CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
- Departamento de Fisiología, Biología Molecular y Celular, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Ana R. Raimondi
- CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
- University of Miami- Center for AIDS Research (UM-CFAR)/Sylvester Comprehensive Cancer Center (CCC) Argentina Consortium for Research and Training in Virally Induced AIDS-Malignancies, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Victoria Medina
- CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
- University of Miami- Center for AIDS Research (UM-CFAR)/Sylvester Comprehensive Cancer Center (CCC) Argentina Consortium for Research and Training in Virally Induced AIDS-Malignancies, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Julian Naipauer
- CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
- University of Miami- Center for AIDS Research (UM-CFAR)/Sylvester Comprehensive Cancer Center (CCC) Argentina Consortium for Research and Training in Virally Induced AIDS-Malignancies, University of Miami Miller School of Medicine, Miami, FL, United States
- Viral Oncology Program, Sylvester Comprehensive Cancer Center, Miami Center for AIDS Research, Department of Microbiology & Immunology, University of Miami, Miami, FL, United States
| | - Enrique A. Mesri
- University of Miami- Center for AIDS Research (UM-CFAR)/Sylvester Comprehensive Cancer Center (CCC) Argentina Consortium for Research and Training in Virally Induced AIDS-Malignancies, University of Miami Miller School of Medicine, Miami, FL, United States
- Viral Oncology Program, Sylvester Comprehensive Cancer Center, Miami Center for AIDS Research, Department of Microbiology & Immunology, University of Miami, Miami, FL, United States
| | - Omar Coso
- CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
- Departamento de Fisiología, Biología Molecular y Celular, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- University of Miami- Center for AIDS Research (UM-CFAR)/Sylvester Comprehensive Cancer Center (CCC) Argentina Consortium for Research and Training in Virally Induced AIDS-Malignancies, University of Miami Miller School of Medicine, Miami, FL, United States
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Li FJ, Long HZ, Zhou ZW, Luo HY, Xu SG, Gao LC. System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol 2022; 13:910292. [PMID: 36105219 PMCID: PMC9465090 DOI: 10.3389/fphar.2022.910292] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System Xc−), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System Xc−/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System Xc−/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System Xc−/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.
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Affiliation(s)
- Feng-Jiao Li
- School of Pharmacy, University of South China, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Hui-Zhi Long
- School of Pharmacy, University of South China, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Zi-Wei Zhou
- School of Pharmacy, University of South China, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Hong-Yu Luo
- School of Pharmacy, University of South China, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Shuo-Guo Xu
- School of Pharmacy, University of South China, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
| | - Li-Chen Gao
- School of Pharmacy, University of South China, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang, China
- *Correspondence: Li-Chen Gao,
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Wang D, Li Y, Ge H, Ghadban T, Reeh M, Güngör C. The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers (Basel) 2022; 14:cancers14163998. [PMID: 36010993 PMCID: PMC9406497 DOI: 10.3390/cancers14163998] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.
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Khodakarami A, Adibfar S, Karpisheh V, Abolhasani S, Jalali P, Mohammadi H, Gholizadeh Navashenaq J, Hojjat-Farsangi M, Jadidi-Niaragh F. The molecular biology and therapeutic potential of Nrf2 in leukemia. Cancer Cell Int 2022; 22:241. [PMID: 35906617 PMCID: PMC9336077 DOI: 10.1186/s12935-022-02660-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 07/19/2022] [Indexed: 02/07/2023] Open
Abstract
NF-E2-related factor 2 (Nrf2) transcription factor has contradictory roles in cancer, which can act as a tumor suppressor or a proto-oncogene in different cell conditions (depending on the cell type and the conditions of the cell environment). Nrf2 pathway regulates several cellular processes, including signaling, energy metabolism, autophagy, inflammation, redox homeostasis, and antioxidant regulation. As a result, it plays a crucial role in cell survival. Conversely, Nrf2 protects cancerous cells from apoptosis and increases proliferation, angiogenesis, and metastasis. It promotes resistance to chemotherapy and radiotherapy in various solid tumors and hematological malignancies, so we want to elucidate the role of Nrf2 in cancer and the positive point of its targeting. Also, in the past few years, many studies have shown that Nrf2 protects cancer cells, especially leukemic cells, from the effects of chemotherapeutic drugs. The present paper summarizes these studies to scrutinize whether targeting Nrf2 combined with chemotherapy would be a therapeutic approach for leukemia treatment. Also, we discussed how Nrf2 and NF-κB work together to control the cellular redox pathway. The role of these two factors in inflammation (antagonistic) and leukemia (synergistic) is also summarized.
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Affiliation(s)
- Atefeh Khodakarami
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Adibfar
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Vahid Karpisheh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shiva Abolhasani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pooya Jalali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Mohammad Hojjat-Farsangi
- Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.,Department of Immunology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. .,Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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Di Giorgio E, Ferino A, Choudhary H, Löffler PMG, D'Este F, Rapozzi V, Tikhomirov A, Shchekotikhin A, Vogel S, Xodo LE. Photosensitization of pancreatic cancer cells by cationic alkyl-porphyrins in free form or engrafted into POPC liposomes: The relationship between delivery mode and mechanism of cell death. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2022; 231:112449. [PMID: 35504235 DOI: 10.1016/j.jphotobiol.2022.112449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/18/2022] [Accepted: 04/21/2022] [Indexed: 06/14/2023]
Abstract
Cationic porphyrins bearing an alkyl side chain of 14 (2b) or 18 (2d) carbons dramatically inhibit proliferation of pancreatic cancer cells following treatment with light. We have compared two different ways of delivering porphyrin 2d: either in free form or engrafted into palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes (L-2d). Cell cytometry shows that while free 2d is taken up by pancreatic cancer cells by active (endocytosis) and passive (membrane fusion) transports, L-2d is internalized solely by endocytosis. Confocal microscopy showed that free 2d co-localizes with the cell membrane and lysosomes, whereas L-2d partly co-localizes with lysosomes and ER. It is found that free 2d inhibits the KRAS-Nrf2-GPX4 axis and strongly triggers lipid peroxidation, resulting in cell death by ferroptosis. By contrast, L-2d does not affect the KRAS-Nrf2-GPX4 axis and activates cell death mainly through apoptosis. Overall, our study demonstrates for the first time that cationic alkyl porphyrins, which have a IC50 ~ 23 nM, activate a dual mechanism of cell death, ferroptosis and apoptosis, where the predominant form depends on the delivery mode.
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Affiliation(s)
- Eros Di Giorgio
- Department of Medicine, Laboratory of Biochemistry, University of Udine, P.le Kolbe 4, 33100 Udine, Italy
| | - Annalisa Ferino
- Department of Medicine, Laboratory of Biochemistry, University of Udine, P.le Kolbe 4, 33100 Udine, Italy
| | - Himanshi Choudhary
- Department of Medicine, Laboratory of Biochemistry, University of Udine, P.le Kolbe 4, 33100 Udine, Italy
| | - Phillip M G Löffler
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark
| | - Francesca D'Este
- Department of Medicine, Laboratory of Biochemistry, University of Udine, P.le Kolbe 4, 33100 Udine, Italy
| | - Valentina Rapozzi
- Department of Medicine, Laboratory of Biochemistry, University of Udine, P.le Kolbe 4, 33100 Udine, Italy
| | | | | | - Stefan Vogel
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark
| | - Luigi E Xodo
- Department of Medicine, Laboratory of Biochemistry, University of Udine, P.le Kolbe 4, 33100 Udine, Italy.
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Xiang Y, Dai S, Li D, Zhu X, Su J, Chen B, Wu M. Brusatol inhibits the invasion and migration of pancreatic cancer cells by suppressing the NRF2/NF-κB/STAT3 signal cascade. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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40
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Philipson E, Engström C, Naredi P, Bourghardt Fagman J. High expression of p62/SQSTM1 predicts shorter survival for patients with pancreatic cancer. BMC Cancer 2022; 22:347. [PMID: 35354432 PMCID: PMC8969328 DOI: 10.1186/s12885-022-09468-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/28/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Accumulation of the signal adaptor protein p62 has been demonstrated in many forms of cancer, including pancreatic ductal adenocarcinoma (PDAC). Although data from experimental studies suggest that p62 accumulation accelerates the development of PDAC, the association between p62 protein expression and survival in PDAC patients is unclear. METHODS Thirty-three tumor specimens from PDAC patients treated by primary surgery were obtained. Immunohistochemical expression of p62, microtubule-associated protein 1A/1B-light chain 3 (LC3), and nuclear factor-erythroid factor 2-related factor 2 (NRF2) in tumor tissue was examined for associations with clinicopathological characteristics and disease-specific survival (DSS). RESULTS There was no association between p62 expression and any of the clinicopathological variables. However, high p62 protein expression in tumor cells was significantly associated with shorter DSS (7 months vs. 29 months, p = 0.017). The hazard ratio for death in patients with high p62 protein expression in tumor cells was 2.88 (95% confidence interval: 1.17-7.11, p = 0.022). In multivariable analysis, high p62 expression was an independent prognostic factor for shorter DSS (p = 0.020) when follow up time was more than 5 years. LC3 and NRF2 staining was not associated with survival or other clinicopathological parameters. CONCLUSION Our results show that high p62 protein expression in tumor cells is associated with shorter survival following pancreatic tumor resection. This association supports a role for p62 as a prognostic marker in patients with PDAC treated by primary surgery.
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Affiliation(s)
- Eva Philipson
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Surgery, Sahlgrenska University Hospital, Sahlgrenska, Vita Stråket 12, paviljong plan 2, SE-413 45, Gothenburg, Sweden
| | - Cecilia Engström
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Surgery, Sahlgrenska University Hospital, Sahlgrenska, Vita Stråket 12, paviljong plan 2, SE-413 45, Gothenburg, Sweden
| | - Peter Naredi
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Surgery, Sahlgrenska University Hospital, Sahlgrenska, Vita Stråket 12, paviljong plan 2, SE-413 45, Gothenburg, Sweden
| | - Johan Bourghardt Fagman
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. .,Department of Surgery, Sahlgrenska University Hospital, Sahlgrenska, Vita Stråket 12, paviljong plan 2, SE-413 45, Gothenburg, Sweden.
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Yang L, Xie HJ, Li YY, Wang X, Liu XX, Mai J. Molecular mechanisms of platinum‑based chemotherapy resistance in ovarian cancer (Review). Oncol Rep 2022; 47:82. [PMID: 35211759 PMCID: PMC8908330 DOI: 10.3892/or.2022.8293] [Citation(s) in RCA: 131] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/14/2022] [Indexed: 12/24/2022] Open
Abstract
Cisplatin is one of the most effective chemotherapy drugs for ovarian cancer, but resistance is common. The initial response to platinum‑based chemotherapy is as high as 80%, but in most advanced patients, final relapse and death are caused by acquired drug resistance. The development of resistance to therapy in ovarian cancer is a significant hindrance to therapeutic efficacy. The resistance of ovarian cancer cells to chemotherapeutic mechanisms is rather complex and includes multidrug resistance, DNA damage repair, cell metabolism, oxidative stress, cell cycle regulation, cancer stem cells, immunity, apoptotic pathways, autophagy and abnormal signaling pathways. The present review provided an update of recent developments in our understanding of the mechanisms of ovarian cancer platinum‑based chemotherapy resistance, discussed current and emerging approaches for targeting these patients and presented challenges associated with these approaches, with a focus on development and overcoming resistance.
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Affiliation(s)
- Ling Yang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Hong-Jian Xie
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Ying-Ying Li
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Xia Wang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Xing-Xin Liu
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan 610041, P.R. China
| | - Jia Mai
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan 610041, P.R. China
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42
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Metformin increases the radiosensitivity of non-small cell lung cancer cells by destabilizing NRF2. Biochem Pharmacol 2022; 199:114981. [DOI: 10.1016/j.bcp.2022.114981] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 12/13/2022]
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Narożna M, Krajka-Kuźniak V, Kleszcz R, Baer-Dubowska W. Indomethacin and Diclofenac Hybrids with Oleanolic Acid Oximes Modulate Key Signaling Pathways in Pancreatic Cancer Cells. Int J Mol Sci 2022; 23:ijms23031230. [PMID: 35163154 PMCID: PMC8835846 DOI: 10.3390/ijms23031230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
Our earlier studies showed that coupling nonsteroidal anti-inflammatory drugs (NSAIDs) with oleanolic acid derivatives increased their anti-inflammatory activity in human hepatoma cells. The aim of this study was to evaluate their effect on the signaling pathways involved in inflammation processes in human pancreatic cancer (PC) cells. Cultured PSN-1 cells were exposed for 24 h (30 µM) to OA oxime (OAO) derivatives substituted with benzyl or morpholide groups and their conjugates with indomethacin (IND) or diclofenac (DCL). The activation of NF-κB and Nrf2 was assessed by the evaluation of the translocation of their active forms into the nucleus and their binding to specific DNA sequences via the ELISA assay. The expression of NF-κB and Nrf2 target genes was evaluated by R-T PCR and Western blot analysis. The conjugation of IND or DCL with OAO derivatives increased cytotoxicity and their effect on the tested signaling pathways. The most effective compound was the DCL hybrid with OAO morpholide (4d). This compound significantly reduced the activation and expression of NF-κB and enhanced the activation and expression of Nrf2. Increased expression of Nrf2 target genes led to reduced ROS production. Moreover, MAPKs and the related pathways were also affected. Therefore, conjugate 4d deserves more comprehensive studies as a potential PC therapeutic agent.
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Affiliation(s)
- Maria Narożna
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcicki Street, 60-781 Poznań, Poland; (M.N.); (V.K.-K.); (R.K.)
- Program in Cell Cycle and Cancer Biology, Oklahoma Medical Research Foundation, 825, NE 13th Street, Oklahoma City, OK 73104, USA
| | - Violetta Krajka-Kuźniak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcicki Street, 60-781 Poznań, Poland; (M.N.); (V.K.-K.); (R.K.)
| | - Robert Kleszcz
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcicki Street, 60-781 Poznań, Poland; (M.N.); (V.K.-K.); (R.K.)
| | - Wanda Baer-Dubowska
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcicki Street, 60-781 Poznań, Poland; (M.N.); (V.K.-K.); (R.K.)
- Correspondence:
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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.
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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
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Role of Nrf2 in Pancreatic Cancer. Antioxidants (Basel) 2021; 11:antiox11010098. [PMID: 35052602 PMCID: PMC8773052 DOI: 10.3390/antiox11010098] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/26/2021] [Accepted: 12/28/2021] [Indexed: 12/18/2022] Open
Abstract
Pancreatic tumors are a serious health problem with a 7% mortality rate worldwide. Inflammatory processes and oxidative stress play important roles in the development of pancreatic diseases/cancer. To maintain homeostasis, a balance between free radicals and the antioxidant system is essential. Nuclear Factor Erythroid 2-Related Factor 2/NFE2L2 (Nrf2) and its negative regulator Kelch-Like ECH-Associated Protein 1 (Keap1) provide substantial protection against damage induced by oxidative stress, and a growing body of evidence points to the canonical and noncanonical Nrf2 signaling pathway as a pharmacological target in the treatment of pancreatic diseases. In this review, we present updated evidence on the activation of the Nrf2 signaling pathway and its importance in pancreatic cancer. Our review covers potential modulators of canonical and noncanonical pathway modulation mechanisms that may have a positive effect on the therapeutic response. Finally, we describe some interesting recent discoveries of novel treatments related to the antioxidant system for pancreatic cancer, including natural or synthetic compounds with therapeutic properties.
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46
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Overview of human 20 alpha-hydroxysteroid dehydrogenase (AKR1C1): Functions, regulation, and structural insights of inhibitors. Chem Biol Interact 2021; 351:109746. [PMID: 34780792 DOI: 10.1016/j.cbi.2021.109746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/28/2021] [Accepted: 11/10/2021] [Indexed: 11/22/2022]
Abstract
Human aldo-keto reductase family 1C1 (AKR1C1) is an important enzyme involved in human hormone metabolism, which is mainly responsible for the metabolism of progesterone in the human body. AKR1C1 is highly expressed and has an important relationship with the occurrence and development of various diseases, especially some cancers related to hormone metabolism. Nowadays, many inhibitors against AKR1C1 have been discovered, including some synthetic compounds and natural products, which have certain inhibitory activity against AKR1C1 at the target level. Here we briefly reviewed the physiological and pathological functions of AKR1C1 and the relationship with the disease, and then summarized the development of AKR1C1 inhibitors, elucidated the interaction between inhibitors and AKR1C1 through molecular docking results and existing co-crystal structures. Finally, we discussed the design ideals of selective AKR1C1 inhibitors from the perspective of AKR1C1 structure, discussed the prospects of AKR1C1 in the treatment of human diseases in terms of biomarkers, pre-receptor regulation and single nucleotide polymorphisms, aiming to provide new ideas for drug research targeting AKR1C1.
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47
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Chen X, Zeh HJ, Kang R, Kroemer G, Tang D. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol 2021; 18:804-823. [PMID: 34331036 DOI: 10.1038/s41575-021-00486-6] [Citation(s) in RCA: 207] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is a devastating gastrointestinal cancer characterized by late diagnosis, limited treatment success and dismal prognosis. Exocrine tumours account for 95% of pancreatic cancers and the most common pathological type is pancreatic ductal adenocarcinoma (PDAC). The occurrence and progression of PDAC involve multiple factors, including internal genetic alterations and external inflammatory stimuli. The biology and therapeutic response of PDAC are further shaped by various forms of regulated cell death, such as apoptosis, necroptosis, ferroptosis, pyroptosis and alkaliptosis. Cell death induced by local or systemic treatments suppresses tumour proliferation, invasion and metastasis. However, unrestricted cell death or tissue damage might result in an inflammation-related immunosuppressive microenvironment, which is conducive to tumour progression or recurrence. The precise extent to which cell death affects PDAC is not yet well described. A growing body of preclinical and clinical studies document significant correlations between mutations (for example, in KRAS and TP53), stress responses (such as hypoxia and autophagy), metabolic reprogramming and chemotherapeutic responses. Here, we describe the molecular machinery of cell death, discuss the complexity and multifaceted nature of lethal signalling in PDAC cells, and highlight the challenges and opportunities for activating cell death pathways through precision oncology treatments.
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Affiliation(s)
- Xin Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Herbert J Zeh
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. .,Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China. .,Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
| | - Daolin Tang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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Bansod S, Dodhiawala PB, Lim KH. Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities. Cancers (Basel) 2021; 13:cancers13215481. [PMID: 34771644 PMCID: PMC8582583 DOI: 10.3390/cancers13215481] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 12/20/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.
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Affiliation(s)
- Sapana Bansod
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; (S.B.); (P.B.D.)
| | - Paarth B. Dodhiawala
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; (S.B.); (P.B.D.)
- Medical Scientist Training Program, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; (S.B.); (P.B.D.)
- Correspondence: ; Tel.: +1-314-362-6157
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Zhou L, Yang C, Zhong W, Wang Q, Zhang D, Zhang J, Xie S, Xu M. Chrysin induces autophagy-dependent ferroptosis to increase chemosensitivity to gemcitabine by targeting CBR1 in pancreatic cancer cells. Biochem Pharmacol 2021; 193:114813. [PMID: 34673014 DOI: 10.1016/j.bcp.2021.114813] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/17/2021] [Accepted: 10/15/2021] [Indexed: 12/26/2022]
Abstract
Recent studies have verified that inducing reactive oxygen species (ROS) is one of the gemcitabine anti-tumor mechanisms of action. Human carbonyl reductase 1 (CBR1) plays an important role in protecting cells against oxidative damage. However, it is unclear whether CBR1 is involved in pancreatic cancer (PC) progression and resistance to gemcitabine. Based on the GEPIA database, we analyzed tumor tissue samples from PC patients using immunohistochemistry (IHC) and revealed that CBR1 was highly expressed in PC tissues and that this was significantly correlated with the clinicopathological features of PC. Genetic inhibition of CBR1 suppressed PC cell proliferation by regulating ROS generation. Furthermore, gemcitabine upregulated CBR1 expression, which could limit the anti-tumor activity of gemcitabine, and attenuation of CBR1 enhanced gemcitabine sensitivity in vitro and in vivo. Additionally, we report that chrysin directly binds to CBR1, which inhibited its enzymatic activity both at the molecular and cellular levels. Inhibition of CBR1 by chrysin increased cellular ROS levels and led to ROS-dependent autophagy, which resulted in the degradation of ferritin heavy polypeptide 1 (FTH1) and an increase in the intracellular free iron level that participates in ferroptosis in PC cells. Finally, our results showed that chrysin enhanced PC sensitivity to gemcitabine by inducing ferroptotic death in vitro and in vivo. Collectively, these findings indicate that CBR1 is a potential therapeutic target for PC treatment. In addition, we elucidated a novel mechanism underlying the anti-tumor effects of chrysin.
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Affiliation(s)
- Ling Zhou
- The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, YanTai, ShanDong 264003, PR China
| | - Chen Yang
- The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, YanTai, ShanDong 264003, PR China
| | - Weilan Zhong
- The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, YanTai, ShanDong 264003, PR China; The Third Peoples Hospital of Qingdao, Huangdao District, Qingdao, Shandong 266400, PR China
| | - Qiaoyun Wang
- The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, YanTai, ShanDong 264003, PR China
| | - Daolai Zhang
- The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, YanTai, ShanDong 264003, PR China
| | - Jiayu Zhang
- The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, YanTai, ShanDong 264003, PR China
| | - Shuyang Xie
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, PR China.
| | - Maolei Xu
- The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, YanTai, ShanDong 264003, PR China.
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50
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Yang J, Xu J, Zhang B, Tan Z, Meng Q, Hua J, Liu J, Wang W, Shi S, Yu X, Liang C. Ferroptosis: At the Crossroad of Gemcitabine Resistance and Tumorigenesis in Pancreatic Cancer. Int J Mol Sci 2021; 22:10944. [PMID: 34681603 PMCID: PMC8539929 DOI: 10.3390/ijms222010944] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/03/2021] [Accepted: 10/05/2021] [Indexed: 12/13/2022] Open
Abstract
The overall five-year survival rate of pancreatic cancer has hardly changed in the past few decades (less than 10%) because of resistance to all known therapies, including chemotherapeutic drugs. In the past few decades, gemcitabine has been at the forefront of treatment for pancreatic ductal adenocarcinoma, but more strategies to combat drug resistance need to be explored. One promising possibility is ferroptosis, a form of a nonapoptotic cell death that depends on intracellular iron and occurs through the accumulation of lipid reactive oxygen species, which are significant in drug resistance. In this article, we reviewed gemcitabine-resistance mechanisms; assessed the relationship among ferroptosis, tumorigenesis and gemcitabine resistance, and explored a new treatment method for pancreatic cancer.
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Affiliation(s)
- Jianhui Yang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Zhen Tan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (J.Y.); (J.X.); (B.Z.); (Z.T.); (Q.M.); (J.H.); (J.L.); (W.W.); (S.S.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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