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Xue J, Li Q, Wang Y, Yin R, Zhang J. Insight into the structure, oligomerization, and the role in drug resistance of human UDP-glucuronosyltransferases. Arch Toxicol 2025; 99:1153-1165. [PMID: 39812829 DOI: 10.1007/s00204-024-03929-6] [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: 10/12/2024] [Accepted: 11/28/2024] [Indexed: 01/16/2025]
Abstract
Human UDP-glucuronosyltransferases (UGTs) are pivotal phase II metabolic enzymes facilitating the transfer of glucuronic acid from UDP-glucuronic acid (UDPGA) to various substrates. UGTs are classic type I transmembrane glycoproteins, mainly localized in the endoplasmic reticulum (ER) membrane. This review comprehensively explores UGTs, encompassing gene expression, functional characteristics, substrate specificity, and metabolic mechanisms. A recent analysis of C-terminal structures, compared with original data, underscores the pivotal role of α3, α4, and β4 functional domains in selectively recognizing diverse glycosyl donors. Accumulating evidence suggests that UGTs function as homo- and heterodimers, with oligomers likely stabilizing UGTs and modulating their activity. The review sheds light on the implications of UGT oligomerization on substrate glucuronidation and the interplay between protein-protein interaction and glucuronidation activity. UGT-mediated drug resistance, often underestimated, emerges as a clinically relevant form of chemical resistance, with delineated outcomes in tumors and other diseases. This review provides a multifaceted exploration of the physiological significance of UGTs, spanning genetics, proteins, oligomerization, drug resistance, and more, offering insights into their metabolic mechanisms. Understanding interactions between UGT isoforms is crucial for predicting drug-drug interactions, preventing drug toxicity, and enabling precision treatment.
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Affiliation(s)
- Jia Xue
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qiuyi Li
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yao Wang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ruxi Yin
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jian Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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2
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Bae T, Kwak MK. Kelch-like ECH-associated Protein 1/Nuclear Factor Erythroid 2-related Factor 2 Pathway and Its Interplay with Oncogenes in Lung Tumorigenesis. J Cancer Prev 2024; 29:89-98. [PMID: 39790220 PMCID: PMC11706728 DOI: 10.15430/jcp.24.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 01/12/2025] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor regulating cellular redox homeostasis, exhibits a complex role in cancer biology. Genetic mutations in the Kelch-like ECH-associated protein 1 (KEAP1)/NRF2 system, which lead to NRF2 hyperactivation, are found in 20% to 30% of lung cancer cases. This review explores the intricate interplay between NRF2 and key oncogenic pathways in lung cancer, focusing on the interaction of KEAP1/NRF2 system with Kirsten rat sarcoma virus (KRAS), tumor protein P53 (TP53), epidermal growth factor receptor (EGFR), and phosphatidylinositol 3-kinases (PI3K)/AKT signaling. While NRF2 activation alone is insufficient to initiate tumorigenesis, it can significantly impact tumor initiation and progression when combined with oncogenic drivers such as KRAS. The review highlights the context-dependent effects of NRF2, from its protective role against chemical carcinogen-induced tumor initiation to its potential promotion of tumor growth in established cancers. These findings suggest the need for nuanced, stage-specific approaches to targeting the NRF2 pathway in cancer therapy.
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Affiliation(s)
- Taegeun Bae
- Integrated Research Institute for Pharmaceutical Sciences, Bucheon, Korea
| | - Mi-Kyoung Kwak
- Integrated Research Institute for Pharmaceutical Sciences, Bucheon, Korea
- College of Pharmacy, The Catholic University of Korea, Bucheon, Korea
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3
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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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Schwarcz S, Kovács P, Nyerges P, Ujlaki G, Sipos A, Uray K, Bai P, Mikó E. The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma. Cell Death Discov 2024; 10:248. [PMID: 38782891 PMCID: PMC11116504 DOI: 10.1038/s41420-024-02023-1] [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: 09/06/2023] [Revised: 05/08/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024] Open
Abstract
Lithocholic acid (LCA) is a secondary bile acid. LCA enters the circulation after bacterial synthesis in the gastrointestinal tract, reaches distantly located cancer cells, and influences their behavior. LCA was considered carcinogenic, but recent studies demonstrated that LCA has antitumor effects. We assessed the possible role of LCA in pancreatic adenocarcinoma. At the serum reference concentration, LCA induced a multi-pronged antineoplastic program in pancreatic adenocarcinoma cells. LCA inhibited cancer cell proliferation and induced mesenchymal-to-epithelial (MET) transition that reduced cell invasion capacity. LCA induced oxidative/nitrosative stress by decreasing the expression of nuclear factor, erythroid 2-like 2 (NRF2) and inducing inducible nitric oxide synthase (iNOS). The oxidative/nitrosative stress increased protein nitration and lipid peroxidation. Suppression of oxidative stress by glutathione (GSH) or pegylated catalase (pegCAT) blunted LCA-induced MET. Antioxidant genes were overexpressed in pancreatic adenocarcinoma and decreased antioxidant levels correlated with better survival of pancreatic adenocarcinoma patients. Furthermore, LCA treatment decreased the proportions of cancer stem cells. Finally, LCA induced total and ATP-linked mitochondrial oxidation and fatty acid oxidation. LCA exerted effects through the farnesoid X receptor (FXR), vitamin D receptor (VDR), and constitutive androstane receptor (CAR). LCA did not interfere with cytostatic agents used in the chemotherapy of pancreatic adenocarcinoma. Taken together, LCA is a non-toxic compound and has antineoplastic effects in pancreatic adenocarcinoma.
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Affiliation(s)
- Szandra Schwarcz
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Patrik Kovács
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Petra Nyerges
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Gyula Ujlaki
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
- HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, 4032, Hungary
| | - Adrienn Sipos
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
- HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, 4032, Hungary
| | - Karen Uray
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Péter Bai
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
- HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Edit Mikó
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary.
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Nguyen V, Taine EG, Meng D, Cui T, Tan W. Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline. Int J Mol Sci 2024; 25:3385. [PMID: 38542359 PMCID: PMC10970276 DOI: 10.3390/ijms25063385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/08/2024] [Accepted: 03/14/2024] [Indexed: 04/17/2024] Open
Abstract
Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-β peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.
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Affiliation(s)
- Vi Nguyen
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA;
| | | | - Dehao Meng
- Applied Physics Program, California State University San Marcos, San Marcos, CA 92096, USA
| | - Taixing Cui
- Dalton Cardiovascular Research Center, Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO 65211, USA;
| | - Wenbin Tan
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA;
- Department of Biomedical Engineering, College of Engineering and Computing, University of South Carolina, Columbia, SC 29208, USA
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Wu K, El Zowalaty AE, Sayin VI, Papagiannakopoulos T. The pleiotropic functions of reactive oxygen species in cancer. NATURE CANCER 2024; 5:384-399. [PMID: 38531982 DOI: 10.1038/s43018-024-00738-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 01/19/2024] [Indexed: 03/28/2024]
Abstract
Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells.
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Affiliation(s)
- Katherine Wu
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
| | - Ahmed Ezat El Zowalaty
- Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Volkan I Sayin
- Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
| | - Thales Papagiannakopoulos
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
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Prabhu SS, Nair AS, Nirmala SV. Multifaceted roles of mitochondrial dysfunction in diseases: from powerhouses to saboteurs. Arch Pharm Res 2023; 46:723-743. [PMID: 37751031 DOI: 10.1007/s12272-023-01465-y] [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: 02/05/2023] [Accepted: 09/19/2023] [Indexed: 09/27/2023]
Abstract
The fact that mitochondria play a crucial part in energy generation has led to the nickname "powerhouses" of the cell being applied to them. They also play a significant role in many other cellular functions, including calcium signalling, apoptosis, and the creation of vital biomolecules. As a result, cellular function and health as a whole can be significantly impacted by mitochondrial malfunction. Indeed, malignancies frequently have increased levels of mitochondrial biogenesis and quality control. Adverse selection exists for harmful mitochondrial genome mutations, even though certain malignancies include modifications in the nuclear-encoded tricarboxylic acid cycle enzymes that generate carcinogenic metabolites. Since rare human cancers with mutated mitochondrial genomes are often benign, removing mitochondrial DNA reduces carcinogenesis. Therefore, targeting mitochondria offers therapeutic options since they serve several functions and are crucial to developing malignant tumors. Here, we discuss the various steps involved in the mechanism of cancer for which mitochondria plays a significant role, as well as the role of mitochondria in diseases other than cancer. It is crucial to understand mitochondrial malfunction to target these organelles for therapeutic reasons. This highlights the significance of investigating mitochondrial dysfunction in cancer and other disease research.
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Affiliation(s)
- Surapriya Surendranath Prabhu
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Aathira Sujathan Nair
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Saiprabha Vijayakumar Nirmala
- Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India.
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Tanaka HY, Nakazawa T, Enomoto A, Masamune A, Kano MR. Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment. Cancers (Basel) 2023; 15:cancers15030724. [PMID: 36765684 PMCID: PMC9913712 DOI: 10.3390/cancers15030724] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/19/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer.
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Affiliation(s)
- Hiroyoshi Y. Tanaka
- Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi 700-8530, Okayama, Japan
| | - Takuya Nakazawa
- Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi 700-8530, Okayama, Japan
| | - Atsushi Enomoto
- Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya-shi 466-8550, Aichi, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai-shi 980-8574, Miyagi, Japan
| | - Mitsunobu R. Kano
- Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi 700-8530, Okayama, Japan
- Correspondence:
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NRF2 in Cancer: Cross-Talk with Oncogenic Pathways and Involvement in Gammaherpesvirus-Driven Carcinogenesis. Int J Mol Sci 2022; 24:ijms24010595. [PMID: 36614036 PMCID: PMC9820659 DOI: 10.3390/ijms24010595] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022] Open
Abstract
Expanding knowledge of the molecular mechanisms at the basis of tumor development, especially the cross-talk between oncogenic pathways, will possibly lead to better tailoring of anticancer therapies. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in cancer progression, not only because of its antioxidant activity but also because it establishes cross-talk with several oncogenic pathways, including Heat Shock Factor1 (HSF1), mammalian target of rapamycin (mTOR), and mutant (mut) p53. Moreover, the involvement of NRF2 in gammaherpesvirus-driven carcinogenesis is particularly interesting. These viruses indeed hijack the NRF2 pathway to sustain the survival of tumor cells in which they establish a latent infection and to avoid a too-high increase of reactive oxygen species (ROS) when these cancer cells undergo treatments that induce viral replication. Interestingly, NRF2 activation may prevent gammaherpesvirus-driven oncogenic transformation, highlighting how manipulating the NRF2 pathway in the different phases of gammaherpesvirus-mediated carcinogenesis may lead to different outcomes. This review will highlight the mechanistic interplay between NRF2 and some oncogenic pathways and its involvement in gammaherpesviruses biology to recapitulate published evidence useful for potential application in cancer therapy.
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Xu H, Wu J, Zhang L, Li Y, Gao L, Cheng Y. The measurement of NRF2 and TP53 in blood expects radiotherapeutic sensitivity in patients with esophageal cancer. Mol Cell Probes 2022; 66:101860. [PMID: 36116599 DOI: 10.1016/j.mcp.2022.101860] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/10/2022] [Accepted: 09/07/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE This study investigates the relationship between the mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and Tumor protein p53 (TP53) in circulating tumor cells (CTC) and sensitivity to radiotherapy in patients with esophageal cancer. To investigate the relationship between cytokines IL-6, CD8+, and NRF2 during patient treatment and their predictive role for treatment. METHODS Radiosensitivity was assessed by measuring a morphological or functional change in the tumor in response to ionizing radiation. Fasting venous anticoagulated blood (EDTA anticoagulation) was drawn from patients, and the Trizol-chloroform two-step method was used for RNA extraction. Data were collected from 45 patients admitted with radiotherapy alone from January 2018 to December 2021. The expression levels of NRF2mRNA (Messenger Ribose Nucleic Acid) and TP53mRNA in CTCs were detected by reverse transcription-polymerase chain reaction (RT-PCR). Pre- and post-treatment changes in IL-6 and CD8+ were recorded. The correlation between their expression level and the clinical stage, radiotherapy sensitivity, and efficacy of patients was analyzed. RESULTS Twenty-six cases were sensitive to radiotherapy, and 19 were resistant, for a radiotherapy sensitivity rate of 58.8%. NRF2mRNA and TP53mRNA values increased in 19 radiotherapy-resistant patients and decreased in 26 radiotherapy-sensitive patients compared with those before radiotherapy (P = 0.001, P＜0.05). The ΔCT values of NRF2mRNA and TP53mRNA before treatment were moderately correlated with prognosis (P < 0.002). Inflammatory cytokine IL-6 was elevated in 22 of 45 patients after radiation, P = 0.04. NRF2 mRNA level was consistently elevated with CD8+ in 10 patients, P = 0.02. CONCLUSIONS The expression of NRF2mRNA and TP53mRNA in the CTCs found in the peripheral blood of patients with esophageal squamous carcinoma was significantly associated with the sensitivity to radiotherapy. NRF2 mRNA level was consistently elevated with CD8+ and IL-6 in patients.
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Affiliation(s)
- Huiqin Xu
- Radiotherapy Center, Qilu hospital of Shandong University, Jinan city, Shandong Province, 25000, China; Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China.
| | - Jinchang Wu
- Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China
| | - Lansheng Zhang
- Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China
| | - Yang Li
- Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China
| | - Liyan Gao
- Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221000, China
| | - Yufeng Cheng
- Radiotherapy Center, Qilu hospital of Shandong University, Jinan city, Shandong Province, 25000, China.
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Moss DY, McCann C, Kerr EM. Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers. Sci Signal 2022; 15:eabj3490. [PMID: 36256706 DOI: 10.1126/scisignal.abj3490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The constitutive activity of mutant KRAS and its downstream signaling pathways induces metabolic rewiring in tumor cells that can promote resistance to existing therapeutics. In this review, we discuss the metabolic pathways that are altered in response to treatment and those that can, in turn, alter treatment efficacy, as well as the role of metabolism in the tumor microenvironment (TME) in dictating the therapeutic response in KRAS-driven cancers. We highlight metabolic targets that may provide clinical opportunities to overcome therapeutic resistance and improve survival in patients with these aggressive cancers.
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Affiliation(s)
- Deborah Y Moss
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE Northern Ireland, UK
| | - Christopher McCann
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE Northern Ireland, UK
| | - Emma M Kerr
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE Northern Ireland, UK
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Abstract
AbstractSestrin2 is a conserved antioxidant, metabolism regulator, and downstream of P53. Sestrin2 can suppress oxidative stress and inflammation, thereby preventing the development and progression of cancer. However, Sestrin2 attenuates severe oxidative stress by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thereby enhancing cancer cells survival and chemoresistance. Sestrin2 inhibits endoplasmic reticulum stress and activates autophagy and apoptosis in cancer cells. Attenuation of endoplasmic reticulum stress and augmentation of autophagy hinders cancer development but can either expedite or impede cancer progression under specific conditions. Furthermore, Sestrin2 can vigorously inhibit oncogenic signaling pathways through downregulation of mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1-alpha (HIF-1α). Conversely, Sestrin2 decreases the cytotoxic activity of T cells and natural killer cells which helps tumor cells immune evasion. Sestrin2 can enhance tumor cells viability in stress conditions such as glucose or glutamine deficiency. Cancer cells can also upregulate Sestrin2 during chemotherapy or radiotherapy to attenuate severe oxidative stress and ER stress, augment autophagy and resist the treatment. Recent studies unveiled that Sestrin2 is involved in the development and progression of several types of human cancer. The effect of Sestrin2 may differ depending on the type of tumor, for instance, several studies revealed that Sestrin2 protects against colorectal cancer, whereas results are controversial regarding lung cancer. Furthermore, Sestrin2 expression correlates with metastasis and survival in several types of human cancer such as colorectal cancer, lung cancer, and hepatocellular carcinoma. Targeted therapy for Sestrin2 or regulation of its expression by new techniques such as non-coding RNAs delivery and vector systems may improve cancer chemotherapy and overcome chemoresistance, metastasis and immune evasion that should be investigated by future trials.
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Zhang J, Xu HX, Cho WCS, Cheuk W, Li Y, Huang QH, Yang W, Xian YF, Lin ZX. Brucein D augments the chemosensitivity of gemcitabine in pancreatic cancer via inhibiting the Nrf2 pathway. J Exp Clin Cancer Res 2022; 41:90. [PMID: 35272669 PMCID: PMC8908700 DOI: 10.1186/s13046-022-02270-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/21/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Gemcitabine (GEM) is the first-line chemotherapeutic drug used to treat pancreatic ductal adenocarcinoma carcinoma (PDAC), but chemoresistance is often encountered clinically. Nrf2, an oxidative stress responsive transcription factor, is an important contributor to chemoresistance and poor prognosis of PDAC. Brucein D (BD), a naturally occurring quassinoid, has been reported to exert anti-tumor effect in several cancers including PDAC. In this study, we aimed to investigate the efficacy of BD and the role of Nrf2 axes on the chemosensitivity of GEM and elucidate the underlying molecular mechanisms. METHODS Analyses of clinical samples of PDAC and GEPIA database were first conducted to identify the expression of Nrf2 in PDAC. We then established cell lines with stable deletion of Nrf2 through transfecting lentivirus into PDAC cells. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the expression of Nrf2 in these cell lines. The effects of BD and Nrf2 axes on PDAC cell proliferation, colony-formation, tumor growth and chemosensitivity were determined both in vitro and in vivo. Orthotopic xenograft and genetically engineered KPC mouse models of PDAC were used to evaluate the anti-pancreatic cancer effects of BD and GEM. RESULTS Nrf2 was highly expressed in PDAC in the clinical samples and GEPIA analysis. Gain- and lost-function study demonstrated that Nrf2 affected the chemosensitivity of GEM on PDAC cells both in vitro and in vivo. We further found that BD effectively inhibited PDAC cell proliferation and enhanced the chemosensitivity of GEM. Mechanistic studies revealed that BD sensitized GEM in PDAC cells through the ubiquitin-proteasome-dependent degradation of Nrf2, and downregulating the Nrf2 pathway. Silencing of Nrf2 plus BD treatment resulted in more potent inhibitory effects of GEM. In contrast, Nrf2 activation attenuated the chemosensitivity of GEM, indicating that the action of BD was Nrf2 dependent. Finally, the efficacy of BD alone and in combination with GEM on PDAC was validated on both orthotopic xenograft and genetically engineered KPC mouse models. CONCLUSIONS BD was able to enhance the chemosensitivity of GEM in PDAC through inhibition of the Nrf2 pathway. Our experimental findings indicate that BD, a potent Nrf2 inhibitor, holds promise for further development into a novel adjuvant therapy for PDAC.
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Affiliation(s)
- Juan Zhang
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong SAR, HK 999077 P.R. China
| | - Hong-Xi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 P.R. China
| | - William Chi Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, P.R. China
| | - Wah Cheuk
- Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, P.R. China
| | - Yang Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 P.R. China
| | - Qiong-Hui Huang
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong SAR, HK 999077 P.R. China
| | - Wen Yang
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong SAR, HK 999077 P.R. China
| | - Yan-Fang Xian
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong SAR, HK 999077 P.R. China
| | - Zhi-Xiu Lin
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong SAR, HK 999077 P.R. China
- Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P. R. China
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14
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Concise Review: Gene of The Month KEAP1-mutant non-small cell lung cancer: the catastrophic failure of a cell-protecting hub. J Thorac Oncol 2022; 17:751-757. [DOI: 10.1016/j.jtho.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/21/2022] [Accepted: 03/15/2022] [Indexed: 11/19/2022]
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15
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Pillai R, Hayashi M, Zavitsanou AM, Papagiannakopoulos T. NRF2: KEAPing Tumors Protected. Cancer Discov 2022; 12:625-643. [PMID: 35101864 DOI: 10.1158/2159-8290.cd-21-0922] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/22/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022]
Abstract
The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance. SIGNIFICANCE: Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.
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Affiliation(s)
- Ray Pillai
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, VA New York Harbor Healthcare System, New York, New York.,Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Perlmutter Cancer Center, New York University School of Medicine, New York, New York
| | - Makiko Hayashi
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York
| | - Anastasia-Maria Zavitsanou
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York
| | - Thales Papagiannakopoulos
- Department of Pathology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York.
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16
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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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Hamada S, Matsumoto R, Masamune A. HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14020411. [PMID: 35053572 PMCID: PMC8773475 DOI: 10.3390/cancers14020411] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/13/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic cancer progression involves interactions between cancer cells and stromal cells in harsh tumor microenvironments, which are characterized by hypoxia, few nutrients, and oxidative stress. Clinically, cancer cells overcome therapeutic interventions, such as chemotherapy and radiotherapy, to continue to survive. Activation of the adaptation mechanism is required for cancer cell survival under these conditions, and it also contributes to the acquisition of the malignant phenotype. Stromal cells, especially pancreatic stellate cells, play a critical role in the formation of a cancer-promoting microenvironment. We here review the roles of key molecules, hypoxia inducible factor-1 and KEAP1-NRF2, in stress response mechanisms for the adaptation to hypoxia and oxidative stress in pancreatic cancer cells and stellate cells. Various cancer-promoting properties associated with these molecules have been identified, and they might serve as novel therapeutic targets in the future. Abstract Pancreatic cancer is intractable due to early progression and resistance to conventional therapy. Dense fibrotic stroma, known as desmoplasia, is a characteristic feature of pancreatic cancer, and develops through the interactions between pancreatic cancer cells and stromal cells, including pancreatic stellate cells. Dense stroma forms harsh tumor microenvironments characterized by hypoxia, few nutrients, and oxidative stress. Pancreatic cancer cells as well as pancreatic stellate cells survive in the harsh microenvironments through the altered expression of signaling molecules, transporters, and metabolic enzymes governed by various stress response mechanisms. Hypoxia inducible factor-1 and KEAP1-NRF2, stress response mechanisms for hypoxia and oxidative stress, respectively, contribute to the aggressive behaviors of pancreatic cancer. These key molecules for stress response mechanisms are activated, both in pancreatic cancer cells and in pancreatic stellate cells. Both factors are involved in the mutual activation of cancer cells and stellate cells, by inducing cancer-promoting signals and their mediators. Therapeutic interventions targeting these pathways are promising approaches for novel therapies. In this review, we summarize the roles of stress response mechanisms, focusing on hypoxia inducible factor-1 and KEAP1-NRF2, in pancreatic cancer. In addition, we discuss the potential of targeting these molecules for the treatment of pancreatic cancer.
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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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Matsumoto R, Hamada S, Tanaka Y, Taguchi K, Yamamoto M, Masamune A. Nuclear Factor Erythroid 2-Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression. J Pharmacol Exp Ther 2021; 379:33-40. [PMID: 34321315 DOI: 10.1124/jpet.121.000744] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/20/2021] [Indexed: 11/22/2022] Open
Abstract
As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated aldehyde dehydrogenase 3a1 (ALDH3A1) in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers. SIGNIFICANCE STATEMENT: We identified nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target aldehyde dehydrogenase 3a1 (ALDH3A1) as novel therapeutic targets in pancreatic cancer. They negatively affect the efficacy of a conventional chemotherapeutic agent, gemcitabine. We confirmed that Nrf2 plays a pivotal role in the induction of ALDH3A1.
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Affiliation(s)
- Ryotaro Matsumoto
- Division of Gastroenterology (R.M., S.H., Y.T., A.M.) and Department of Medical Biochemistry (K.T., M.Y.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shin Hamada
- Division of Gastroenterology (R.M., S.H., Y.T., A.M.) and Department of Medical Biochemistry (K.T., M.Y.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yu Tanaka
- Division of Gastroenterology (R.M., S.H., Y.T., A.M.) and Department of Medical Biochemistry (K.T., M.Y.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Taguchi
- Division of Gastroenterology (R.M., S.H., Y.T., A.M.) and Department of Medical Biochemistry (K.T., M.Y.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masayuki Yamamoto
- Division of Gastroenterology (R.M., S.H., Y.T., A.M.) and Department of Medical Biochemistry (K.T., M.Y.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology (R.M., S.H., Y.T., A.M.) and Department of Medical Biochemistry (K.T., M.Y.), Tohoku University Graduate School of Medicine, Sendai, Japan
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20
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Tanaka Y, Hamada S, Matsumoto R, Taguchi K, Yamamoto M, Masamune A. Nrf2 expression in pancreatic stellate cells promotes progression of cancer. Am J Physiol Gastrointest Liver Physiol 2021; 321:G378-G388. [PMID: 34405729 DOI: 10.1152/ajpgi.00120.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
It was previously identified that systemic Nrf2 deletion attenuates pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in α-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs from Nrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium of Nrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells coinjected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those coinjected with Nrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.NEW & NOTEWORTHY This study identified that Nrf2 contributes to PSC activation. Nrf2 deletion in PSCs resulted in attenuation of cancer-promoting role. Nrf2 in PSCs could be an attractive therapeutic target in pancreatic cancer.
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Affiliation(s)
- Yu Tanaka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryotaro Matsumoto
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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21
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Grattarola M, Cucci MA, Roetto A, Dianzani C, Barrera G, Pizzimenti S. Post-translational down-regulation of Nrf2 and YAP proteins, by targeting deubiquitinases, reduces growth and chemoresistance in pancreatic cancer cells. Free Radic Biol Med 2021; 174:202-210. [PMID: 34364982 DOI: 10.1016/j.freeradbiomed.2021.08.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/29/2021] [Accepted: 08/05/2021] [Indexed: 12/15/2022]
Abstract
The intrinsic chemoresistance of pancreatic ductal adenocarcinoma (PDAC) represents the main obstacle in treating this aggressive malignancy. It has been observed that high antioxidant levels and upregulated Nrf2 and the YAP protein expression can be involved in PDAC chemoresistance. The mechanisms of Nrf2 and YAP increase need to be clarified. We chose a panel of PDAC cell lines with diverse sensitivity to cisplatin and gemcitabine. In PANC-1 chemoresistant cells, we found a low level of oxidative stress and high levels of Nrf2 and YAP protein expressions and their respective targets. On the contrary, in CFPAC-1 chemosensitive cells, we found high levels of oxidative stress and low level of these two proteins, as well as their respective targets. In MiaPaCa-2 cells with a middle chemoresistance, we observed intermediate features. When Nrf2 and YAP were inhibited in PANC-1 cells by Ailanthone, a plant extract, we observed a reduction of viability, thus sustaining the role of these two proteins in maintaining the PDAC chemoresistance. We then delved into the mechanisms of the Nrf2 and YAP protein upregulation in chemoresistance, discovering that it was at a post-translational level since the mRNA expressions did not match the protein levels. Treatments of PANC-1 cells with the proteasome inhibitor MG-132 and the protein synthesis inhibitor cycloheximide further confirmed this observation. The expression of DUB3 and OTUD1 deubiquitinases, involved in the control of Nrf2 and YAP protein level, respectively, was also investigated. Both protein expressions were higher in PANC-1 cells, intermediate in MiaPaCa-2 cells, and lower in CFPAC-1 cells. When DUB3 or OTUD1 were silenced, both Nrf2 and YAP expressions were downregulated. Importantly, in deubiquitinase-silenced cells, we observed a great reduction of proliferation and a higher sensitivity to gemcitabine treatment, suggesting that DUB3 and OTUD1 can represent a suitable target to overcome chemoresistance in PDAC cells.
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Affiliation(s)
- Margherita Grattarola
- Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125, Torino, Italy
| | - Marie Angèle Cucci
- Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125, Torino, Italy
| | - Antonella Roetto
- Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125, Torino, Italy
| | - Chiara Dianzani
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125, Turin, Italy
| | - Giuseppina Barrera
- Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125, Torino, Italy
| | - Stefania Pizzimenti
- Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125, Torino, Italy.
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22
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Huang W, Xue L, Xu H, Kong Z, Xu J, Zhao H, Nie Y. Diagnostic value of neuronal pentraxin II methylation in patients with pancreatic cancer: Meta-analysis. Int J Clin Pract 2021; 75:e14443. [PMID: 34105851 DOI: 10.1111/ijcp.14443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/01/2020] [Accepted: 05/24/2021] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a devasting disease of which mortality almost parallels its incidence. PC tissue may express aberrantly methylated neuronal pentraxin II (NPTX2), but it is unclear what the consequences of this are. METHODS We systematically searched PubMed, Web of Science, the Chinese National Knowledge Infrastructure (CNKI), from inception to July 15, 2020, to identify if the detection of methylated NPTX2 have sufficient sensitivity and specificity to identify PC from other benign pancreatic diseases. RESULTS Majority of the studies obtained samples from pancreatic juice by endoscopy or surgery and composed of population with chronic pancreatitis, benign cystic lesion, intraductal papillary mucinous neoplasm, and healthy controls. Our results demonstrated that the diagnostic value of methylated NPTX2 is of widely various sensitivity and specificity and it shown higher specificity in differentiate PC from benign diseases. The lab method of quantitative real-time methylation-specific PCR (QMSP) has higher specificity than real-time methylation-specific PCR (MSP) in detecting the indicator. CONCLUSIONS NPTX2 methylation could serve as a promising molecular biomarker for pancreatic cancer diagnosis, for its high diagnostic value in differentiating pancreatic cancer from benign pancreatic disease with the lab method. The variable sensitivity of methylated NPTX2 was multifactorial, and it must be promoted before applied as screening test in clinical practice. Furthermore, experiments on methylated NPTX2 were needed to expanded for lower the heterogeneity.
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Affiliation(s)
- Wenqi Huang
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - LiFeng Xue
- Department of Gastroenterology, People's Hospital of Shenzhen, Guangzhou, China
| | - Haoming Xu
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhiqian Kong
- Dongguan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Dongguan, China
| | - Jing Xu
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Hailan Zhao
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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Mallya K, Gautam SK, Aithal A, Batra SK, Jain M. Modeling pancreatic cancer in mice for experimental therapeutics. Biochim Biophys Acta Rev Cancer 2021; 1876:188554. [PMID: 33945847 DOI: 10.1016/j.bbcan.2021.188554] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/19/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy that is characterized by early metastasis, low resectability, high recurrence, and therapy resistance. The experimental mouse models have played a central role in understanding the pathobiology of PDAC and in the preclinical evaluation of various therapeutic modalities. Different mouse models with targetable pathological hallmarks have been developed and employed to address the unique challenges associated with PDAC progression, metastasis, and stromal heterogeneity. Over the years, mouse models have evolved from simple cell line-based heterotopic and orthotopic xenografts in immunocompromised mice to more complex and realistic genetically engineered mouse models (GEMMs) involving multi-gene manipulations. The GEMMs, mostly driven by KRAS mutation(s), have been widely accepted for therapeutic optimization due to their high penetrance and ability to recapitulate the histological, molecular, and pathological hallmarks of human PDAC, including comparable precursor lesions, extensive metastasis, desmoplasia, perineural invasion, and immunosuppressive tumor microenvironment. Advanced GEMMs modified to express fluorescent proteins have allowed cell lineage tracing to provide novel insights and a new understanding about the origin and contribution of various cell types in PDAC pathobiology. The syngeneic mouse models, GEMMs, and target-specific transgenic mice have been extensively used to evaluate immunotherapies and study therapy-induced immune modulation in PDAC yielding meaningful results to guide various clinical trials. The emerging mouse models for parabiosis, hepatic metastasis, cachexia, and image-guided implantation, are increasingly appreciated for their high translational significance. In this article, we describe the contribution of various experimental mouse models to the current understanding of PDAC pathobiology and their utility in evaluating and optimizing therapeutic modalities for this lethal malignancy.
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Affiliation(s)
- Kavita Mallya
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Abhijit Aithal
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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Wang Z, Li Z, Xu H, Liao Y, Sun C, Chen Y, Sheng M, Lan Q, Wang Z. PSMD12 promotes glioma progression by upregulating the expression of Nrf2. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:700. [PMID: 33987398 PMCID: PMC8106014 DOI: 10.21037/atm-21-1481] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background Glioma is the most common and aggressive primary brain tumor in adults. Proteasome 26S subunit, non-ATPase 12 (PSMD12), an important subunit in the 26S proteasome, is known to be involved in the growth and apoptosis of breast cancer cells. However, its exact function and underlying molecular mechanisms in glioma remain unknown. Methods PSMD12 expression was detected in glioma tissue specimens by immunohistochemistry (IHC) and TCGA database. Overexpression and down-regulation of PSMD12 and Nrf2 were induced in glioma cell lines, and CCK-8 and Transwell assays were used to detect cell proliferation and invasion evaluation, respectively. Xenograft model was used to observe the effect of knockdown of PSMD12 on tumor growth. Immunohistochemical assays and TCGA database were conducted to reveal the relationships between PSMD12 expression and Nrf2. Finally, Western blot and related biological function experiments were used to explore the mechanism of PSMD12 regulating the glioma progression and Nrf2. Results We revealed that PSMD12 is upregulated in glioma, especially in high-grade glioma, by analyzing bioinformatics data and clinical specimens. PSMD12 upregulation was associated with poor prognosis in glioma patients. Knockdown of PSMD12 inhibited the growth of glioma cells in vitro and in vivo and decreased their invasion ability, whereas PSMD12 overexpression had the opposite effect. Mechanistic analysis revealed that PSMD12 increased the expression of nuclear factor E2-related factor 2 (Nrf2), which functions as a tumor promoter in the development of glioma. Similar to PSMD12, Nrf2, which exhibited a strong positive correlation with PSMD12, was abnormally elevated in glioma tissues and contributed to worse overall survival (OS). Nrf2 overexpression reversed the inhibitory effects induced by PSMD12 knockdown. Finally, PSMD12 enhanced the proliferation and invasion of glioma cells via Akt signaling-mediated Nrf2 expression. Conclusions These results suggest that PSMD12 is considered to be a crucial regulator of the development and progression of glioma and may serve as a potential biomarker or therapeutic target for the treatment of glioma.
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Affiliation(s)
- Zhongyong Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhiyu Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hui Xu
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yun Liao
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chao Sun
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanming Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Minfeng Sheng
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Qing Lan
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhong Wang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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25
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Hamada S, Matsumoto R, Tanaka Y, Taguchi K, Yamamoto M, Masamune A. Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition. Int J Mol Sci 2021; 22:1870. [PMID: 33672789 PMCID: PMC7918355 DOI: 10.3390/ijms22041870] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.
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Affiliation(s)
- Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
| | - Ryotaro Matsumoto
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
| | - Yu Tanaka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
| | - Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; (K.T.); (M.Y.)
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; (K.T.); (M.Y.)
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; (R.M.); (Y.T.); (A.M.)
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26
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Ma S, McGuire MH, Mangala LS, Lee S, Stur E, Hu W, Bayraktar E, Villar-Prados A, Ivan C, Wu SY, Yokoi A, Dasari SK, Jennings NB, Liu J, Lopez-Berestein G, Ram P, Sood AK. Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype. Cell Rep 2021; 34:108726. [PMID: 33567287 PMCID: PMC7957825 DOI: 10.1016/j.celrep.2021.108726] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 04/14/2020] [Accepted: 01/15/2021] [Indexed: 02/07/2023] Open
Abstract
Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications. Ma et al. report that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to stromal fibroblasts. The packaging of GOF p53 into small EVs is regulated by HSP90. Small EVs with GOF p53 activate Nrf2-mediated pathways in fibroblasts and induce their conversion to a cancer-associated phenotype.
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Affiliation(s)
- Shaolin Ma
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Michael H McGuire
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Lingegowda S Mangala
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Sanghoon Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Elaine Stur
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Wen Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Emine Bayraktar
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Alejandro Villar-Prados
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Cristina Ivan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Sherry Y Wu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Akira Yokoi
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Santosh K Dasari
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Nicholas B Jennings
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Jinsong Liu
- Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Prahlad Ram
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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27
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Purohit V, Wang L, Yang H, Li J, Ney GM, Gumkowski ER, Vaidya AJ, Wang A, Bhardwaj A, Zhao E, Dolgalev I, Zamperone A, Abel EV, Magliano MPD, Crawford HC, Diolaiti D, Papagiannakopoulos TY, Lyssiotis CA, Simeone DM. ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer. Genes Dev 2021; 35:218-233. [PMID: 33446568 PMCID: PMC7849366 DOI: 10.1101/gad.344184.120] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/25/2020] [Indexed: 01/04/2023]
Abstract
Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.
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Affiliation(s)
- Vinee Purohit
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Lidong Wang
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Huibin Yang
- Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Jiufeng Li
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Gina M Ney
- Department of Pediatric Oncology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Erica R Gumkowski
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Akash J Vaidya
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Annie Wang
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
- Department of Surgery, New York University, New York, New York 10016, USA
| | - Amit Bhardwaj
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Ende Zhao
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Igor Dolgalev
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Andrea Zamperone
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Ethan V Abel
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Marina Pasca Di Magliano
- Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
- Department of Cell and Developmental Biology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Howard C Crawford
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Daniel Diolaiti
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
| | - Thales Y Papagiannakopoulos
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
- Department of Pathology, New York University, New York, New York 10016, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109, USA
| | - Diane M Simeone
- Perlmutter Cancer Center, New York University, New York, New York 10016, USA
- Department of Surgery, New York University, New York, New York 10016, USA
- Department of Pathology, New York University, New York, New York 10016, USA
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28
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Beeraka NM, Bovilla VR, Doreswamy SH, Puttalingaiah S, Srinivasan A, Madhunapantula SV. The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers. Cancers (Basel) 2021; 13:cancers13020281. [PMID: 33466626 PMCID: PMC7828646 DOI: 10.3390/cancers13020281] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Aim of this review is to provide an overview on (a) Fructosamine-3-Kinase (FN3K) and its role in regulating Nuclear Factor Erythorid-2-Related Factor-2 (Nrf2); (b) the role of glycation and deglycation mechanisms in modulating the functional properties of proteins, in particular, the Nrf2; (c) the dual role of Nrf2 in the prevention and treatment of cancers. Since controlling the glycation of Nrf2 is one of the key mechanisms determining the fate of a cell; whether to get transformed into a cancerous one or to stay as a normal one, it is important to regulate Nrf2 and deglycating FN3K using pharmacological agents. Inhibitors of FN3K are being explored currently to modulate Nrf2 activity thereby control the cancers. Abstract Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa–B (NF-κB), tumor necrosis factor (TNF)-α, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state.
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Affiliation(s)
- Narasimha M. Beeraka
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
| | - Venugopal R. Bovilla
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
- Public Health Research Institute of India (PHRII), Mysuru, Karnataka 570020, India
| | - Shalini H. Doreswamy
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
| | - Sujatha Puttalingaiah
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
| | - Asha Srinivasan
- Division of Nanoscience and Technology, Faculty of Life Sciences, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India;
| | - SubbaRao V. Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India; (N.M.B.); (V.R.B.); (S.H.D.); (S.P.)
- Special Interest Group in Cancer Biology and Cancer Stem Cells, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India
- Correspondence: ; Tel.: +91-810-527-8621
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29
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Ashrafizadeh M, Bakhoda MR, Bahmanpour Z, Ilkhani K, Zarrabi A, Makvandi P, Khan H, Mazaheri S, Darvish M, Mirzaei H. Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms With Emphasis on Pancreatic Cancer. Front Chem 2020; 8:829. [PMID: 33195038 PMCID: PMC7593821 DOI: 10.3389/fchem.2020.00829] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is the most lethal malignancy of the gastrointestinal tract. Due to its propensity for early local and distant spread, affected patients possess extremely poor prognosis. Currently applied treatments are not effective enough to eradicate all cancer cells, and minimize their migration. Besides, these treatments are associated with adverse effects on normal cells and organs. These therapies are not able to increase the overall survival rate of patients; hence, finding novel adjuvants or alternatives is so essential. Up to now, medicinal herbs were utilized for therapeutic goals. Herbal-based medicine, as traditional biotherapeutics, were employed for cancer treatment. Of them, apigenin, as a bioactive flavonoid that possesses numerous biological properties (e.g., anti-inflammatory and anti-oxidant effects), has shown substantial anticancer activity. It seems that apigenin is capable of suppressing the proliferation of cancer cells via the induction of cell cycle arrest and apoptosis. Besides, apigenin inhibits metastasis via down-regulation of matrix metalloproteinases and the Akt signaling pathway. In pancreatic cancer cells, apigenin sensitizes cells in chemotherapy, and affects molecular pathways such as the hypoxia inducible factor (HIF), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1). Herein, the biotherapeutic activity of apigenin and its mechanisms toward cancer cells are presented in the current review to shed some light on anti-tumor activity of apigenin in different cancers, with an emphasis on pancreatic cancer.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Mohammad Reza Bakhoda
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Bahmanpour
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khandan Ilkhani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey
| | - Pooyan Makvandi
- Centre for Micro-BioRobotics, Istituto Italiano di Tecnologia, Pisa, Italy.,Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Samaneh Mazaheri
- Department of Analytical Chemistry, Faculty of Chemistry, University of Kashan, Kashan, Iran
| | - Maryam Darvish
- Department of Medical Biotechnology, Faculty of Medicine, Arak University of Medical Science, Arak, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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30
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Sun Q, Ye Z, Qin Y, Fan G, Ji S, Zhuo Q, Xu W, Liu W, Hu Q, Liu M, Zhang Z, Xu X, Yu X. Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis. Oncogene 2020; 39:6572-6588. [PMID: 32929153 DOI: 10.1038/s41388-020-01452-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 07/29/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023]
Abstract
Evidence suggests that tripartite motif-containing 2 (TRIM2) is associated with carcinogenic effects in several malignancies. However, the expression patterns and roles of TRIM2 in pancreatic cancer are rarely studied. Our study demonstrated that TRIM2 was expressed in a high percentage of pancreatic tumors. High TRIM2 expression was negatively correlated with the outcome of pancreatic cancer. TRIM2 silencing significantly inhibited the proliferation, migration, invasion, and in vivo tumorigenicity of pancreatic cancer cells. Regarding the mechanism involved, TRIM2 activated ROS-related E2-related factor 2 (NRF2)/antioxidant response element (ARE) signaling and the integrin/focal adhesion kinase (FAK) pathway. Treatment of pancreatic cancer cells with the antioxidant N-acetyl-L-cysteine decreased ROS activity and expression level of NRF2 and ITGB7. Increased translocation of NRF2 protein into nucleus further rescued the inhibited ITGB7 transcription. Moreover, NRF2 bound to the potential ARE on the promoter region and enhanced the transcriptional activity of ITGB7, indicating the bridging effect of NRF2 between the two signaling pathways. In summary, our study provides evidence that upregulated TRIM2 in pancreatic cancer predicts short survival for pancreatic cancer patients. TRIM2 accelerates pancreatic cancer progression via the ROS-related NRF2/ITGB7/FAK axis.
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Affiliation(s)
- Qiqing Sun
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Zeng Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Guixiong Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Qifeng Zhuo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Wenyan Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Wensheng Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Qiangsheng Hu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Mengqi Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Zheng Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 200032, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, 200032, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, 200032, Shanghai, China.
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31
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Luo Y, Ma J, Lu W. The Significance of Mitochondrial Dysfunction in Cancer. Int J Mol Sci 2020; 21:ijms21165598. [PMID: 32764295 PMCID: PMC7460667 DOI: 10.3390/ijms21165598] [Citation(s) in RCA: 205] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023] Open
Abstract
As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of apoptosis. Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, oxidative stress, or aberrant oncogene and tumor suppressor signaling, has been observed in a wide spectrum of human cancers. In this review, we summarize mitochondrial dysfunction induced by these alterations that promote human cancers.
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Affiliation(s)
- Yongde Luo
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China
- Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;
- Correspondence: (Y.L.); (W.L.)
| | - Jianjia Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;
| | - Weiqin Lu
- Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;
- Correspondence: (Y.L.); (W.L.)
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Kim EJ, Kim YJ, Lee HI, Jeong SH, Nam HJ, Cho JH. NRF2 Knockdown Resensitizes 5-Fluorouracil-Resistant Pancreatic Cancer Cells by Suppressing HO-1 and ABCG2 Expression. Int J Mol Sci 2020; 21:E4646. [PMID: 32629871 PMCID: PMC7369955 DOI: 10.3390/ijms21134646] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/11/2020] [Accepted: 06/25/2020] [Indexed: 12/16/2022] Open
Abstract
Chemoresistance is a leading cause of morbidity and mortality in patients with pancreatic cancer and remains an obstacle to successful treatment. The antioxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (NRF2), which plays important roles in tumor angiogenesis and invasiveness, is upregulated in pancreatic ductal adenocarcinoma (PDAC), where it correlates with poor survival. Here, we investigated the role of NRF2 in two 5-Fluourouracil-resistant (5-FUR) PDAC cell lines: BxPC-3 and CFPAC-1. Levels of NRF2 and antioxidants, such as heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and superoxide dismutase 2 (SOD2), were higher in the chemoresistant cells than in their chemosensitive counterparts. Expression of epithelial mesenchymal transition (EMT) markers, stemness markers, including Nanog, Oct4, and CD133, and that of the drug transporter ATP binding cassette, subfamily G, member A2 (ABCG2) was also upregulated in 5-FUR PDAC cells. NRF2 knockdown reversed 5-FU resistance of PDAC cells via suppression of ABCG2 and HO-1. In summary, these data indicate that NRF2 is a potential target for resensitizing 5-FUR PDAC cells to 5-FU to improve treatment outcomes in patients with pancreatic cancer.
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Affiliation(s)
- Eui Joo Kim
- Division of Gastroenterology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea; (E.J.K.); (Y.J.K.); (H.I.L.); (H.J.N.)
| | - Yoon Jae Kim
- Division of Gastroenterology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea; (E.J.K.); (Y.J.K.); (H.I.L.); (H.J.N.)
| | - Hye In Lee
- Division of Gastroenterology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea; (E.J.K.); (Y.J.K.); (H.I.L.); (H.J.N.)
| | - Seok-Hoo Jeong
- Division of Gastroenterology, Department of Internal Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon 22711, Korea;
| | - Hyo Jung Nam
- Division of Gastroenterology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea; (E.J.K.); (Y.J.K.); (H.I.L.); (H.J.N.)
| | - Jae Hee Cho
- Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea
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D'Orazi G, Garufi A, Cirone M. Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 interferes with homeodomain-interacting protein kinase 2/p53 activity to impair solid tumors chemosensitivity. IUBMB Life 2020; 72:1634-1639. [PMID: 32593231 DOI: 10.1002/iub.2334] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 12/20/2022]
Abstract
Resistance to chemotherapy represents a major hurdle to successful cancer treatment. A key role for efficient response to anticancer therapies is played by TP53 oncosuppressor gene that indeed is mutated in 50% of human cancers or inactivated at protein level in the remaining 50%. Homeodomain-interacting protein kinase 2 (HIPK2) is the wild-type p53 (wtp53) apoptotic activator, and its inhibition by hypoxia or hyperglycemia may contribute to tumor chemoresistance mainly by impairing p53 apoptotic activity. Another important molecule able to induce chemoresistance is nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) transcription factor, whose activation by oxidative and/or electrophilic stress regulates a transcriptional antioxidant program allowing cancer cells to adapt and survive to stresses. NRF2 may shift from cytoprotective to tumor-promoting function, according to tumor phases. NRF2 may crosstalk with both wtp53 and mutant p53 (mutp53), inhibiting the wtp53 apoptotic function and strengthening the mutp53 oncogenic function. NRF2 has also been shown to induce HIPK2 mRNA expression cooperating in inducing cytoprotection. Although HIPK2, p53, and NRF2 have been individually extensively studied, their interplay has not been clearly addressed yet. On the basis of the background and our results, we aim at hypothesizing the unexpected pro-survival activity played by the NRF2/HIPK2/p53 interplay that can be hijacked by cancer cells to bypass drugs cytotoxicity.
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Affiliation(s)
- Gabriella D'Orazi
- Department of Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Alessia Garufi
- Department of Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy.,Department of Medical Sciences, University 'G. d'Annunzio', Chieti, Italy
| | - Mara Cirone
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.,Laboratory affiliated to Pasteur Institute, Italy-Foundation Cenci Bolognetti, Rome, Italy
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34
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Sun W, Zhang W, Yu J, Lu Z, Yu J. Inhibition of Nrf2 might enhance the anti-tumor effect of temozolomide in glioma cells via inhibition of Ras/Raf/MEK signaling pathway. Int J Neurosci 2020; 131:975-983. [PMID: 32378973 DOI: 10.1080/00207454.2020.1766458] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Glioblastoma (GBM) is the most common aggressive primary cancer occurring in the brain tissue. GBM accounts 16% of primary brain tumors and half of gliomas. Additionally, the incidence of GBM is increases with aging, and reaches the peak at the age of 75 to 84 years. The survival of patients with GBM remains at a low level, only less than 5% patients diagnosed with GBM survive for 5 years. Temozolomide (TMZ) is a DNA alkylating agent and is currently a first line chemotherapeutic treatment for GBM. TMZ combined with radiation therapy has been shown to prolong the overall survival (OS) to 14.6 months compared with 12.1 months for radiation therapy alone. NF-E2-related factor 2 (Nrf2) is a transcription factor that contains seven functional domains. The binding of Keap1 to Nrf2 is a central regulator of the cellular defense mechanism against environmental stresses. METHODS First, Nrf2 overexpression and inhibition models were constructed in U251 cells using transfection. The percentage of viable cells was detected using the MTT assay. Then, the expression of the HO-1 regulator was detected using qPCR, and the concentrations of oxidative stress related factors were detected using ELISAs. The levels of proteins related to oxidative stress and the Ras/Raf/MEK signaling pathway was detected using western blotting analysis. RESULTS We initially established Nrf2 inhibition and activation cell models in U251 cells and found that the inhibition of Nrf2 expression decreased the mRNA and protein levels of the anti-oxidative enzymes, as well as the secretion of these enzymes into the cellular microenvironment. These effects might be mediated by the inhibition of Ras/Raf/MEK signaling pathway, leading to the inhibition of cellular proliferation. CONCLUSIONS Inhibition of Nrf2 expression might enhance the effect of TMZ on the treatment of GBM and might be a new therapeutic strategy.
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Affiliation(s)
- Wei Sun
- Department of Neurosurgery, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Weihua Zhang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianyong Yu
- Department of Pharmacy, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Zhihui Lu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianhua Yu
- Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, China
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Zhu J, Zhu S, Yu Q, Wu Y. LncRNA FAM66C inhibits pancreatic cancer progression by sponging miR-574-3p. Transl Cancer Res 2020; 9:1806-1817. [PMID: 35117528 PMCID: PMC8798657 DOI: 10.21037/tcr.2020.02.24] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 01/18/2020] [Indexed: 12/12/2022]
Abstract
Background Pancreatic cancer is an extensively concerned human malignancy around the globe, yet the potential therapeutic target remains to be further determined. MicroRNA and LncRNA have been reported to be involved in progression of pancreatic cancer, while the biological role of microRNA-574-3p (miR-574-3p) and FAM66C in pancreatic cancer development is poorly investigated. Methods Quantitative real-time PCR (qPCR) analysis was employed to detect the expression of miR-574-3p and FAM66C in pancreatic normal or cancerous tissues and cells. The proliferative and apoptosis signaling molecules were also examined via qPCR and western blot separately. Additionally, cell proliferation and apoptosis assay were performed via CCK8, colony formation and Annexin V-FITC apoptosis assay. Interaction between miR-574-3p and FAM66C was interrogated by luciferase reporter assay and RNA immunoprecipitation. Even more, a pancreatic cancer xenograft mice assay was implemented to illustrate the coordinating role of miR-574-3p and FAM66C in pancreatic cancer proliferation. Results We found that levels of miR-574-3p were significantly higher in cancer tissues and cells compared to normal (P<0.05). Remarkably, the results indicated that depletion of miR-574-3p inhibited proliferation and promoted apoptosis of human pancreatic cancer cell lines. Additionally, FAM66C was demonstrated to interact with miR-574-3p and inhibit its expression. Significantly, FAM66C was proved to act as a tumor suppressor role via inhibiting cell proliferation and promoting cell apoptosis in pancreatic cancer. Moreover, FAM66C coordinated with miR-574-3p to regulate progression of xenograft tumor in the nude mice. Conclusions FAM66C-miR-574-3p axis mediates progression of pancreatic and might be the promising therapeutic target for pancreatic cancer patients.
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Affiliation(s)
- Jiangang Zhu
- Department of Hepato-Biliary-Pancreatic Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, China
| | - Sheng Zhu
- Department of Hepato-Biliary-Pancreatic Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, China
| | - Qiang Yu
- Department of Hepato-Biliary-Pancreatic Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, China
| | - Yong Wu
- Department of Hepato-Biliary-Pancreatic Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, China
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Ayres Pereira M, Chio IIC. Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies. Genes (Basel) 2019; 11:E6. [PMID: 31861620 PMCID: PMC7016631 DOI: 10.3390/genes11010006] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/11/2019] [Accepted: 12/17/2019] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is an extremely aggressive disease with a high metastatic potential. Most patients are diagnosed with metastatic disease, at which the five-year survival rate is only 3%. A better understanding of the mechanisms that drive metastasis is imperative for the development of better therapeutic interventions. Here, we take the reader through our current knowledge of the parameters that support metastatic progression in pancreatic ductal adenocarcinoma, and the experimental models that are at our disposal to study this process. We also describe the advantages and limitations of these models to study the different aspects of metastatic dissemination.
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Affiliation(s)
| | - Iok In Christine Chio
- Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA;
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37
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Qin JJ, Cheng XD, Zhang J, Zhang WD. Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review. Cell Commun Signal 2019; 17:121. [PMID: 31511020 PMCID: PMC6740038 DOI: 10.1186/s12964-019-0435-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 09/02/2019] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.
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Affiliation(s)
- Jiang-Jiang Qin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China. .,Zhejiang Cancer Hospital, Hangzhou, 310022, China.
| | | | - Jia Zhang
- Shanxi Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Wei-Dong Zhang
- School of Pharmacy, Naval Medical University, 325 Guohe Road, Yangpu District, Shanghai, 200433, China. .,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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38
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Iida-Norita R, Kawamura M, Suzuki Y, Hamada S, Masamune A, Furukawa T, Sato Y. Vasohibin-2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma. Cancer Sci 2019; 110:2296-2308. [PMID: 31074083 PMCID: PMC6609860 DOI: 10.1111/cas.14041] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/28/2019] [Accepted: 05/08/2019] [Indexed: 12/28/2022] Open
Abstract
Vasohibin-2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL-KrasG12D ; LSL-Trp53R172H ; Pdx-1-Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2-knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2-deficient mice, metastasis was significantly decreased in Vash2-deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2-induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2-deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.
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Affiliation(s)
- Rie Iida-Norita
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Minaho Kawamura
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Yasuhiro Suzuki
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toru Furukawa
- Department of Histopathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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Gilardini Montani MS, Cecere N, Granato M, Romeo MA, Falcinelli L, Ciciarelli U, D'Orazi G, Faggioni A, Cirone M. Mutant p53, Stabilized by Its Interplay with HSP90, Activates a Positive Feed-Back Loop Between NRF2 and p62 that Induces Chemo-Resistance to Apigenin in Pancreatic Cancer Cells. Cancers (Basel) 2019; 11:cancers11050703. [PMID: 31121848 PMCID: PMC6562395 DOI: 10.3390/cancers11050703] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/16/2019] [Accepted: 05/18/2019] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive cancers whose prognosis is worsened by the poor response to the current chemotherapies. In this study, we investigated the cytotoxic effect of Apigenin, against two pancreatic cell lines, namely Panc1 and PaCa44, harboring different p53 mutations. Apigenin is a flavonoid widely distributed in nature that displays anti-inflammatory and anticancer properties against a variety of cancers. Here we observed that Apigenin exerted a stronger cytotoxic effect against Panc1 cell line in comparison to PaCa44. Searching for mechanisms responsible for such different effect, we found that the higher cytotoxicity of Apigenin correlated with induction of higher level of intracellular ROS, reduction of mutant (mut) p53 and HSP90 expression and mTORC1 inhibition. Interestingly, we found that mutp53 was stabilized by its interplay with HSP90 and activates a positive feed-back loop between NRF2 and p62, up-regulating the antioxidant response and reducing the cytotoxicity of Apigenin. These results suggest that targeting the molecules involved in the mTOR-HSP90-mutp53-p62-NRF2-antioxidant response axis could help to overcome the chemo-resistance of pancreatic cancer to Apigenin.
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Affiliation(s)
- Maria Saveria Gilardini Montani
- Department of Experimental Medicine, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
| | - Nives Cecere
- Department of Experimental Medicine, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
| | - Marisa Granato
- Department of Experimental Medicine, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
| | - Maria Anele Romeo
- Department of Experimental Medicine, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
| | - Luca Falcinelli
- Department of Experimental Medicine, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
| | - Umberto Ciciarelli
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Gabriella D'Orazi
- Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy.
- Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", 66100 Chieti, Italy.
| | - Alberto Faggioni
- Department of Experimental Medicine, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
| | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy.
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Mutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression. Cancers (Basel) 2019; 11:cancers11050614. [PMID: 31052524 PMCID: PMC6563084 DOI: 10.3390/cancers11050614] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 04/27/2019] [Accepted: 05/01/2019] [Indexed: 02/07/2023] Open
Abstract
The capability of cancer cells to manage stress induced by hypoxia, nutrient shortage, acidosis, redox imbalance, loss of calcium homeostasis and exposure to drugs is a key factor to ensure cancer survival and chemoresistance. Among the protective mechanisms utilized by cancer cells to cope with stress a pivotal role is played by the activation of heat shock proteins (HSP) response, anti-oxidant response induced by nuclear factor erythroid 2-related factor 2 (NRF2), the hypoxia-inducible factor-1 (HIF-1), the unfolded protein response (UPR) and autophagy, cellular processes strictly interconnected. However, depending on the type, intensity or duration of cellular stress, the balance between pro-survival and pro-death pathways may change, and cell survival may be shifted into cell death. Mutations of p53 (mutp53), occurring in more than 50% of human cancers, may confer oncogenic gain-of-function (GOF) to the protein, mainly due to its stabilization and interaction with the above reported cellular pathways that help cancer cells to adapt to stress. This review will focus on the interplay of mutp53 with HSPs, NRF2, UPR, and autophagy and discuss how the manipulation of these interconnected processes may tip the balance towards cell death or survival, particularly in response to therapies.
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Potential Applications of NRF2 Inhibitors in Cancer Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8592348. [PMID: 31097977 PMCID: PMC6487091 DOI: 10.1155/2019/8592348] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 02/10/2019] [Accepted: 02/28/2019] [Indexed: 02/07/2023]
Abstract
The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.
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Khader S, Thyagarajan A, Sahu RP. Exploring Signaling Pathways and Pancreatic Cancer Treatment Approaches Using Genetic Models. Mini Rev Med Chem 2019; 19:1112-1125. [PMID: 30924420 DOI: 10.2174/1389557519666190327163644] [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: 12/03/2018] [Revised: 03/12/2019] [Accepted: 03/19/2019] [Indexed: 11/22/2022]
Abstract
Despite available treatment options, the overall survival rates of pancreatic cancer patients remain dismal. Multiple counter-regulatory pathways have been identified and shown to be involved in interfering with the efficacy of therapeutic agents. In addition, various known genetic alterations in the cellular signaling pathways have been implicated in affecting the growth and progression of pancreatic cancer. Nevertheless, the significance of other unknown pathways is yet to be explored, which provides the rationale for the intervention of new approaches. Several experimental genetic models have been explored to define the impact of key signaling cascades, and their mechanisms in the pathophysiology as well as treatment approaches of pancreatic cancer. The current review highlights the recent updates, and significance of such genetic models in the therapeutic efficacy of anti-tumor agents including the standard chemotherapeutic agents, natural products, cell signaling inhibitors, immunebased therapies and the combination of these approaches in pancreatic cancer.
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Affiliation(s)
- Shorooq Khader
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH 45345, United States
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH 45345, United States
| | - Ravi P Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH 45345, United States
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Kari E, Teppo HR, Haapasaari KM, Kuusisto MEL, Lemma A, Karihtala P, Pirinen R, Soini Y, Jantunen E, Turpeenniemi-Hujanen T, Kuittinen O. Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP. J Clin Pathol 2019; 72:316-321. [PMID: 30755497 PMCID: PMC6580789 DOI: 10.1136/jclinpath-2018-205584] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 01/09/2023]
Abstract
AIMS Oxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown. METHODS Diagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome. RESULTS Nuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival. CONCLUSIONS Nrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group.
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Affiliation(s)
- Esa Kari
- Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland .,Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
| | - Hanna-Riikka Teppo
- Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.,Department of Pathology, Oulu University Hospital, Oulu, Finland
| | | | - Milla Elvi Linnea Kuusisto
- Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.,Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
| | - Aurora Lemma
- Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
| | - Peeter Karihtala
- Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.,Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
| | - Risto Pirinen
- Department of Pathology, North Karelia Central Hospital, Joensuu, Finland
| | - Ylermi Soini
- Department of Pathology and Forensic Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Esa Jantunen
- Department of Internal Medicine, Institute of Clinical Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Taina Turpeenniemi-Hujanen
- Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.,Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
| | - Outi Kuittinen
- Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.,Department of Oncology, Kuopio University Hospital, Kuopio, Finland
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Karihtala P, Porvari K, Soini Y, Eskelinen M, Juvonen P, Haapasaari KM. Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival. Oncology 2018; 96:164-170. [PMID: 30537722 DOI: 10.1159/000494274] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 10/02/2018] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Protein levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) have been proposed as prognostic factors in pancreatic ductal adenocarcinomas (PDACs). These cellular redox-state-regulating enzymes are targeted by several microRNAs, including miR-93 and miR-200a. METHODS We assessed mRNA levels of Nrf2 and Keap1 and tissue expression of miR-93 and miR-200a in 51 patients with surgically treated PDAC. Expression levels were separately measured in malignant cells and adjacent benign cells. RESULTS Keap1 and Nrf2 mRNA expression levels in cancer cells were lower than in adjacent benign tissue (Wilcoxon's test; p = 0.0015 and p = 0.000032, respectively). Conversely, miR-93 expression was higher in cancer cells than in adjacent benign tissue (p = 0.00082). Low levels of miR-93 and miR-200a in cancer cells were associated with poorer differentiation (p = 0.004 and p = 0.002, respectively). In univariate survival analysis, benign-tissue levels of miR-200a above the median predicted better relapse-free survival (RFS) (p = 0.045). CONCLUSIONS High miR-93 and miR-200a levels in cancer cells of PDAC were associated with better differentiation, and miR-200a expression in benign tissue with excellent RFS. Keap1 and Nrf2 mRNA levels showed prominent down-regulation in cancerous versus benign tissue, but they were not associated with disease aggressiveness or outcome.
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Affiliation(s)
- Peeter Karihtala
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland,
| | - Katja Porvari
- Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Ylermi Soini
- Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Matti Eskelinen
- Department of Surgery, Kuopio University Hospital and School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Petri Juvonen
- Department of Surgery, Kuopio University Hospital and School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Kirsi-Maria Haapasaari
- Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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Ding S, Hou X, Wang F, Wang G, Tan X, Liu Y, Zhou Y, Qiu H, Sun E, Jiang N, Li Z, Song J, Feng L, Jia X. Regulation of Eclipta prostrata L. components on cigarette smoking-induced autophagy of bronchial epithelial cells via keap1-Nrf2 pathway. ENVIRONMENTAL TOXICOLOGY 2018; 33:811-820. [PMID: 29726624 DOI: 10.1002/tox.22567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 04/02/2018] [Accepted: 04/10/2018] [Indexed: 06/08/2023]
Abstract
Cigarette smoking extract (CSE)-induced autophagic injury has been regarded as an important contributor to the pathogenesis of lung cancer. We previously found that Eclipta prostrata L. component (CCE) reduced CSE-induced bronchial epithelial cells damage. However, the mechanism remains unknown. Human normal bronchial epithelial cells (NHBE) were exposed to CSE to establish stress model. Nrf2-siRNA and Keap1-siRNA transfection were performed. mRFP-GFP-LC3 dual fluorescence and transmission electron microscopy were used to observe the autophagic characteristics. CCE prevented CSE-induced Nrf2 transfer into cytoplasm and up-regulated Keap1 level of NHBE cells. Furthermore, CCE significantly increased p-p16, p-p21 and p-p53 phosphorylation levels in Nrf2-siRNA- or Keap1-siRNA-transfected cells. As demonstrated by transmission electron microscopy and mRFP-GFP-LC3 dual fluorescence assays, CCE mitigated autophagic injury, and also down-regulated autophagy-related Beclin-1, LC3II/LC3I ratio, Atg5 and ATF4 levels. Our findings showed the attenuation of CCE on CSE-induced NHBE cells injury was associated with Nrf-2-mediated oxidative signaling pathway.
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Affiliation(s)
- Shumin Ding
- School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, People's Republic of China
| | - Xuefeng Hou
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, People's Republic of China
| | - Fujing Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, People's Republic of China
| | - Gang Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, People's Republic of China
| | - Xiaobin Tan
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
| | - Ying Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, People's Republic of China
| | - Yuanli Zhou
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
| | - Huihui Qiu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
| | - E Sun
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
| | - Nan Jiang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, People's Republic of China
| | - Zihao Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
| | - Jie Song
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
| | - Liang Feng
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
- Chinese Materia Medica Department, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Xiaobin Jia
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, People's Republic of China
- Chinese Materia Medica Department, China Pharmaceutical University, Nanjing, People's Republic of China
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Hamada S, Shimosegawa T, Taguchi K, Nabeshima T, Yamamoto M, Masamune A. Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma. Am J Physiol Gastrointest Liver Physiol 2018; 314:G65-G74. [PMID: 28971839 DOI: 10.1152/ajpgi.00228.2017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system has a wide variety of effects in addition to the oxidative stress response, such as growth promotion and chemoresistance of cancer cells. Nrf2 is constitutively activated in most cancer cells. However, the activation of Nrf2 together with oncogenic mutations does not always result in cancer promotion. K-rasLSL-G12D/+:: p53LSL-R172H/+:: Pdx-1-Cre (KPC) mice are an established model of pancreatic cancer that specifically express mutants of both K-ras and p53 in the pancreas by using Pdx-1-Cre. We here generated Pdx-1-Cre::K-rasLSL-G12D/+:: Keap1fl/fl (KC::Keap1) and KPC:: Keap1fl/fl (KPC::Keap1) mice in which Nrf2 is constitutively activated by Keap1 deletion. KC::Keap1 and KPC::Keap1 mice started to die or showed obvious weakness at approximately around 40 days after birth. Histological examination revealed that KC::Keap1 and KPC::Keap1 mice did not develop pancreatic cancer but, instead, progressive atrophy of the pancreatic parenchyma. In these mice, amylase-positive acinar cells as well as insulin- and glucagon-positive islet cells were decreased and surrounded by fibrotic tissues. KC::Keap1 and KPC::Keap1 mice presented lower body weight and glucose levels than C::Keap1 mice, presumably resulting from pancreatic exocrine insufficiency. Histological changes were not obvious in C::Keap1 and PC::Keap1 mice. The presence of the p53 mutation did not affect the phenotypes in KC::Keap1 mice. Heterologous or homologous Nrf2 deletion ( Nrf2+/- or Nrf2-/-) rescued the pancreatic phenotypes, weight loss, and hypoglycemia in KC::Keap1 mice, suggesting that Nrf2 is a major downstream target of Keap1. In conclusion, simultaneous K-ras activation and Keap1 deletion caused progressive atrophy of the pancreatic parenchyma in mice. NEW & NOTEWORTHY Aberrant activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system usually promotes carcinogenesis, and we assumed that simultaneous activation of K-ras and Nrf2 might promote pancreatic carcinogenesis. Conditional expression of mutant K-ras and Keap1 deletion did not result in pancreatic cancer development. Instead, these mice developed progressive loss of pancreatic parenchyma, accompanied by body weight loss and hypoglycemia, presumably because of pancreatic exocrine insufficiency. Nrf2 activation by Keap1 deletion concomitant with K-ras activation cause pancreatic atrophy.
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Affiliation(s)
- Shin Hamada
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Tatsuhide Nabeshima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
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