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1
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Wang M, Gao C, Lessing DJ, Chu W. Saccharomyces cerevisiae SC-2201 Attenuates AOM/DSS-Induced Colorectal Cancer by Modulating the Gut Microbiome and Blocking Proinflammatory Mediators. Probiotics Antimicrob Proteins 2025; 17:1523-1535. [PMID: 38329696 DOI: 10.1007/s12602-024-10228-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2024] [Indexed: 02/09/2024]
Abstract
Colorectal cancer is the third most common cancer in the world today, and studies have shown that the ratio of Candida to Saccharomyces cerevisiae increased, and the abundance of S. cerevisiae in the intestines of patients with colorectal cancer decreased, which suggests that there is an imbalance in the proportion of fungi in the intestines of patients with colorectal cancer. The objective of this study was to screen S. cerevisiae isolate from traditional Chinese fermentation starters and assess its ability to ameliorate dysbiosis and to alleviate the carcinogenic process of azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice model. S. cerevisiae strain SC-2201 was isolated and exhibited probiotic properties, including the ability to survive in an acidic pH environment and in the presence of bile salts in the gastrointestinal tract, as well as antioxidant activities. Oral administration of S. cerevisiae SC-2201 not only alleviated weight loss but also reduced colonic shortening and histological damage in azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice. Furthermore, the administration of S. cerevisiae SC-2201 suppressed the expression of proinflammatory mediators, such as interleukin-1β, interleukin-6, cyclooxygenase-2, vascular endothelial growth factor, nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3. Specifically, the analysis of gut bacteriome showed a significant decrease in Bacteroidota and Campylobacterota levels, as well as an increase in Proteobacteria level in the colorectal cancer group, which was alleviated by supplementation with S. cerevisiae SC-2201. The analysis of the mycobiome revealed a significant increase in the levels of Basidiomycota, Apiosordaria, Naganishia, and Taphrina genera in the colorectal cancer group, which were alleviated after supplementation with S. cerevisiae SC-2201. However, the levels of Xenoramularia, Entoloma, and Keissleriella were significantly increased after administration with S. cerevisiae SC-2201. Overall, the findings of this study demonstrate that S. cerevisiae SC-2201 possesses potential probiotic properties and can effectively attenuate the development of colorectal cancer, highlighting its cancer-preventive potential. This is the first report of a S. cerevisiae strain isolated from traditional Chinese fermentation starters which showed good probiotic properties, and mitigated azoxymethane/dextran sodium sulfate-induced colorectal cancer by modulating the gut microbiome and blocking proinflammatory mediators in mice.
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Affiliation(s)
- Minyu Wang
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Jiangsu Province, Nanjing, 210009, People's Republic of China
| | - Chongzheng Gao
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Jiangsu Province, Nanjing, 210009, People's Republic of China
| | - Duncan James Lessing
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Jiangsu Province, Nanjing, 210009, People's Republic of China
| | - Weihua Chu
- School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Jiangsu Province, Nanjing, 210009, People's Republic of China.
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2
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Guo L, Li X. Nurse night shift work and risk of gastrointestinal cancers. Front Public Health 2025; 13:1532623. [PMID: 40356833 PMCID: PMC12066619 DOI: 10.3389/fpubh.2025.1532623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
The prevalence of night-shift employment is on the rise among full-time and part-time workers globally. Those engaged in night-shift work encounter various biological challenges, including exposure to artificial light during nighttime and disruptions to their circadian rhythms. These factors, along with changes in daily routines and activities, may pose significant risks to the health of night workers. Notably, the number of individuals working overtime or on night shifts has increased across various sectors, particularly in transportation, healthcare, and manufacturing. The International Agency for Research on Cancer (IARC) has classified night-shift work as probably carcinogenic to humans (IARC Group 2A). Subsequent research has identified several potential mechanisms through which night-shift work may contribute to carcinogenicity: (1) disruption of circadian rhythms, (2) suppression of melatonin levels due to nighttime light exposure, (3) physiological alterations, (4) lifestyle changes, and (5) reduced vitamin D levels resulting from inadequate sunlight exposure. Colorectal cancer (CRC) poses a significant public health challenge, ranking as the second leading cause of cancer-related death worldwide in 2020. Other than CRC, other gastrointestinal cancers are also creating a great global health issue because of their morbidity and mortality rates. In this review, we highlight the role of night shifts in disturbing circadian rhythm and how this action leads to carcinogenesis in the GI tract.
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Affiliation(s)
- Lin Guo
- Medical Simulated Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Xiaojun Li
- School of Nursing, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
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3
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Liu X, Zhang J, Yi T, Li H, Tang X, Liu D, Wu D, Li Y. Decoding tumor angiogenesis: pathways, mechanisms, and future directions in anti-cancer strategies. Biomark Res 2025; 13:62. [PMID: 40251641 PMCID: PMC12007322 DOI: 10.1186/s40364-025-00779-x] [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: 11/26/2024] [Accepted: 04/13/2025] [Indexed: 04/20/2025] Open
Abstract
Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.
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Affiliation(s)
- Xueru Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Juan Zhang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Ting Yi
- Department of Trauma Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Hui Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Xing Tang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Dan Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Daichao Wu
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China.
| | - Yukun Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China.
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4
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Sasi N, Preetha D, Iyyappan S, Selvamurugan N. Circular RNAs: Emerging regulators of signaling pathways in epithelial-mesenchymal transition and angiogenesis during breast cancer progression. Semin Oncol 2025; 52:152340. [PMID: 40220369 DOI: 10.1016/j.seminoncol.2025.152340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/01/2025] [Accepted: 03/06/2025] [Indexed: 04/14/2025]
Abstract
Circular RNAs (circRNAs) have emerged as important regulators of gene expression and cellular activities, and abnormalities in circRNAs in breast cancer have been linked to important biological processes like epithelial-mesenchymal transition (EMT) and angiogenesis, both essential for tumor metastasis. EMT facilitates the transition of epithelial cancer cells into a mesenchymal phenotype, enhancing their invasive and migratory capabilities, while angiogenesis promotes tumor progression by forming new blood vessels. CircRNAs also interact with microRNAs to regulate signaling pathways such as TGF-β, Wnt/-catenin, and VEGF. Besides EMT and angiogenesis, studies have identified that circRNAs affect metabolic reprogramming, chemoresistance, tumor microenvironment remodeling, and immunological evasion. Thus, circRNAs play a multifaceted role in the development of breast cancer. They hold potential as non-invasive biomarkers and therapeutic targets due to their high stability, resistance to exonuclease degradation, abundance in body fluids, and diverse expression patterns across different tissues. This review summarizes and critically assesses existing understanding of the functional roles and molecular processes of circRNAs in controlling EMT and angiogenesis during breast cancer progression.
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Affiliation(s)
- Nivruthi Sasi
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Tamil Nadu, India
| | - Dilipkumar Preetha
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Tamil Nadu, India
| | - Saranya Iyyappan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Tamil Nadu, India
| | - Nagarajan Selvamurugan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Tamil Nadu, India.
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Mahmoud MO, Al-Hamid HA, Hassan NF, El-Ansary MR, Gomaa SB. Linagliptin Mitigates DMH-Induced Colorectal Cancer in Rats: Crosstalk Between NFAT and IL-6/JAK2/STAT3/NF-κB Signaling Hubs. J Biochem Mol Toxicol 2025; 39:e70206. [PMID: 40070168 DOI: 10.1002/jbt.70206] [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: 09/07/2024] [Revised: 01/30/2025] [Accepted: 03/02/2025] [Indexed: 05/13/2025]
Abstract
Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer-related deaths globally. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti-inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2-dimethylhydrazine (DMH)-induced CRC via modulation of NFAT-mediated IL-6 and JAK2/STAT3/NF-κB signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8-week duration. Twenty-four Wistar rats were segregated into three groups of eight rats each; normal control, DMH-induced CRC and DMH + linagliptin (10 mg/kg; p.o). Linagliptin attenuated DMH-induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF-κB) induced by DMH which is highlighted using immunohistochemistry analysis. The anti-inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T-cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin-6 (IL-6) and cyclooxygenase-2 (COX-2) levels. Linagliptin mitigate the protein expression of DMH-activated oncogenic janus-activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B-cell lymphoma 2 (Bcl-2) and a significant elevation in Bcl-2-associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT-mediated IL-6 with JAK2/STAT3/NF-κB signaling cascades.
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Affiliation(s)
- Mohamed O Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Hager Abd Al-Hamid
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Noha F Hassan
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona R El-Ansary
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Safaa B Gomaa
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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6
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Bahrami A, Khalaji A, Bahri Najafi M, Sadati S, Raisi A, Abolhassani A, Eshraghi R, Khaksary Mahabady M, Rahimian N, Mirzaei H. NF-κB pathway and angiogenesis: insights into colorectal cancer development and therapeutic targets. Eur J Med Res 2024; 29:610. [PMID: 39702532 DOI: 10.1186/s40001-024-02168-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/21/2024] [Indexed: 12/21/2024] Open
Abstract
Colorectal cancer (CRC) is currently ranked as the third most common type of cancer, contributing significantly to mortality and morbidity worldwide. Epigenetic and genetic changes occurred during CRC progression resulted in the cell proliferation, cancer progression, angiogenesis, and invasion. Angiogenesis is one of the crucial steps during cancer progression required for the delivery of essential nutrients to cancer cells and removes metabolic waste. During angiogenesis, different molecules are secreted from tumoral cells to trigger vascular formation including epidermal growth factor and the vascular endothelial growth factor (VEGF). The production and regulation of the secretion of these molecules are modulated by different subcellular pathways such as NF-κB. NF-κB is involved in regulation of different homeostatic pathways including apoptosis, cell proliferation, inflammation, differentiation, tumor migration, and angiogenesis. Investigation of different aspects of this pathway and its role in angiogenesis could provide a comprehensive overview about the underlying mechanisms and could be used for development of further therapeutic targets. In this review of literature, we comprehensively reviewed the current understanding and potential of NF-κB-related angiogenesis in CRC. Moreover, we explored the treatments that are based on the NF-κB pathway.
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Affiliation(s)
- Ashkan Bahrami
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majed Bahri Najafi
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sina Sadati
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Arash Raisi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Reza Eshraghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Neda Rahimian
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, 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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7
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Zhou Y, Lin S, Zhong X, Huang F, Huang J, Xu L. Oleanolic acid combined with aspirin plays antitumor roles in colorectal cancer via the Akt/NFκB/IκBα/COX2 pathway. Cell Death Discov 2024; 10:504. [PMID: 39695129 DOI: 10.1038/s41420-024-02223-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 07/16/2024] [Accepted: 10/21/2024] [Indexed: 12/20/2024] Open
Abstract
Among the common malignancies, colorectal cancer (CRC) is often resistant to chemotherapy because of drug resistance and severe toxicity. Currently, aspirin is one of the most promising CRC chemopreventive drugs, both for primary prevention and for reducing the chance of recurrence and metastasis following radical surgery in patients with early-stage CRC. Oleanolic acid is a potential antineoplastic drug that has an antagonistic effect on many kinds of tumors. Network pharmacology, molecular docking, and in vitro experiments were performed to investigate whether OA combined with aspirin can enhance the anticancer effects of aspirin. As indicated by the network pharmacology results, oleanolic acid and aspirin can regulate multiple signaling pathways through multiple target proteins, including NFκB1\IκBα\PTGS2\MAPK3\PIK3CA. A series of cellular experiments demonstrated for the first time that oleanolic acid synergistically enhances aspirin to inhibit the proliferation and invasion of HCT116 and HT29 cells and induce S-phase arrest by regulating Akt/NFκB/IκBα/COX2 signaling pathway, thus synergistically enhancing the ability of aspirin to promote apoptosis of colorectal cancer cells. This study provides a novel approach to the use of fresh medications for the treatment of colorectal cancer and offers a theoretical foundation for the potential creation of aspirin derivatives based on oleanolic acid.
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Affiliation(s)
- Yulv Zhou
- Department of Chinese Medicine and Anorectology, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Shengnan Lin
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Xinzhu Zhong
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Fang Huang
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China
| | - Jinxiang Huang
- Department of Neurosurgery, The First Affiliated Hospital of Naval Medical University (Changhai Hospital), Naval Medical University, Shanghai, China.
| | - Luning Xu
- Department of Clinical Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical University, Sanming City, Fujian Province, China.
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8
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Brockmueller A, Ruiz de Porras V, Shakibaei M. Curcumin and its anti-colorectal cancer potential: From mechanisms of action to autophagy. Phytother Res 2024; 38:3525-3551. [PMID: 38699926 DOI: 10.1002/ptr.8220] [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: 01/03/2024] [Revised: 04/06/2024] [Accepted: 04/10/2024] [Indexed: 05/05/2024]
Abstract
Colorectal cancer (CRC) development and progression, one of the most common cancers globally, is supported by specific mechanisms to escape cell death despite chemotherapy, including cellular autophagy. Autophagy is an evolutionarily highly conserved degradation pathway involved in a variety of cellular processes, such as the maintenance of cellular homeostasis and clearance of foreign bodies, and its imbalance is associated with many diseases. However, the role of autophagy in CRC progression remains controversial, as it has a dual function, affecting either cell death or survival, and is associated with cellular senescence in tumor therapy. Indeed, numerous data have been presented that autophagy in cancers serves as an alternative to cell apoptosis when the latter is ineffective or in apoptosis-resistant cells, which is why it is also referred to as programmed cell death type II. Curcumin, one of the active constituents of Curcuma longa, has great potential to combat CRC by influencing various cellular signaling pathways and epigenetic regulation in a safe and cost-effective approach. This review discusses the efficacy of curcumin against CRC in vitro and in vivo, particularly its modulation of autophagy and apoptosis in various cellular pathways. While clinical studies have assessed the potential of curcumin in cancer prevention and treatment, none have specifically examined its role in autophagy. Nonetheless, we offer an overview of potential correlations to support the use of this polyphenol as a prophylactic or co-therapeutic agent in CRC.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Vicenç Ruiz de Porras
- CARE Program, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain
- Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Barcelona, Spain
- GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
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McKenzie M, Lian GY, Pennel KA, Quinn JA, Jamieson NB, Edwards J. NFκB signalling in colorectal cancer: Examining the central dogma of IKKα and IKKβ signalling. Heliyon 2024; 10:e32904. [PMID: 38975078 PMCID: PMC11226910 DOI: 10.1016/j.heliyon.2024.e32904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 05/20/2024] [Accepted: 06/11/2024] [Indexed: 07/09/2024] Open
Abstract
The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway's overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKβ, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKβ inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC.
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Affiliation(s)
- Molly McKenzie
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Guang-Yu Lian
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Kathryn A.F. Pennel
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Jean A. Quinn
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Nigel B. Jamieson
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
| | - Joanne Edwards
- School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1BD, UK
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10
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Długosz-Pokorska A, Janecki T, Janecka A, Gach-Janczak K. New uracil analog as inhibitor/modulator of ABC transporters or/and NF-κB in taxol-resistant MCF-7/Tx cell line. J Cancer Res Clin Oncol 2024; 150:328. [PMID: 38914845 PMCID: PMC11196363 DOI: 10.1007/s00432-024-05833-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/03/2024] [Indexed: 06/26/2024]
Abstract
PURPOSE The global increase in breast cancer cases necessitates ongoing exploration of advanced therapies. Taxol (Tx), an initial breast cancer treatment, induces mitotic arrest but faces limitations due to side effects and the development of resistance. Addressing Tx resistance involves understanding the complex molecular mechanisms, including alterations in tubulin dynamics, NF-κB signaling, and overexpression of ABC transporters (ABCB1 and ABCG2), leading to multidrug resistance (MDR). METHODS Real-time PCR and ELISA kits were used to analyze ABCB1, ABCG2 and NF-κB gene and protein expression levels, respectively. An MDR test assessed the resistance cell phenotype. RESULTS MCF-7/Tx cells exhibited a 24-fold higher resistance to Tx. Real-time PCR and ELISA analysis revealed the upregulation of ABCB1, ABCG2, and NF-κB. U-359 significantly downregulated both ABCB1 and ABCG2 gene and protein levels. Co-incubation with Tx and U-359 further decreased the mRNA and protein expression of these transporters. The MDR test indicated that U-359 increased MDR dye retention, suggesting its potential as an MDR inhibitor. U-359 and Tx, either individually or combined, modulated NF-κBp65 protein levels. CONCLUSION The development of a Taxol-resistant MCF-7 cell line provided valuable insights. U-359 demonstrated effectiveness in reducing the expression of ABC transporters and NF-κB, suggesting a potential solution for overcoming multidrug resistance in breast cancer cells. The study recommends a strategy to enhance the sensitivity of cancer cells to chemotherapy by integrating U-359 with traditional drugs.
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MESH Headings
- Humans
- Paclitaxel/pharmacology
- Drug Resistance, Neoplasm/drug effects
- NF-kappa B/metabolism
- MCF-7 Cells
- Female
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/metabolism
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Antineoplastic Agents, Phytogenic/pharmacology
- Drug Resistance, Multiple/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
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Affiliation(s)
- Angelika Długosz-Pokorska
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
| | - Tomasz Janecki
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Lodz, Poland
| | - Anna Janecka
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Katarzyna Gach-Janczak
- Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
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11
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Ibrahim OM, Kalinski P. Breaking Barriers: Modulation of Tumor Microenvironment to Enhance Bacillus Calmette-Guérin Immunotherapy of Bladder Cancer. Cells 2024; 13:699. [PMID: 38667314 PMCID: PMC11049012 DOI: 10.3390/cells13080699] [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: 02/16/2024] [Revised: 04/13/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
The clinical management of bladder cancer continues to present significant challenges. Bacillus Calmette-Guérin (BCG) immunotherapy remains the gold standard of treatment for non-muscle invasive bladder cancer (NMIBC), but many patients develop recurrence and progression to muscle-invasive disease (MIBC), which is resistant to BCG. This review focuses on the immune mechanisms mobilized by BCG in bladder cancer tumor microenvironments (TME), mechanisms of BCG resistance, the dual role of the BCG-triggered NFkB/TNFα/PGE2 axis in the regulation of anti-tumor and tumor-promoting aspects of inflammation, and emerging strategies to modulate their balance. A better understanding of BCG resistance will help develop new treatments and predictive biomarkers, paving the way for improved clinical outcomes in bladder cancer patients.
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Affiliation(s)
- Omar M. Ibrahim
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Pawel Kalinski
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
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Szymaszkiewicz A, Mierzejewski M, Januszkiewicz E, Machelak W, Talar M, Włodarczyk J, Świerczyński M, Kordek R, Fichna J, Zielińska M. The role of bidirectional communication between the adipokines and the endogenous opioid system in an experimental mouse model of colitis-associated colorectal cancer. Pharmacol Rep 2024; 76:112-126. [PMID: 38236555 DOI: 10.1007/s43440-023-00566-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of death globally. Multiple factors may contribute to the pathogenesis of CRC, including the abnormalities in the functioning of the endogenous opioid system (EOS) or adiponectin-related signaling. The aim of our study was to evaluate if differences in the expression of opioid receptors (ORs) influence the development of CRC and if modulation of adiponectin receptors using AdipoRon, a selective AdipoR1 receptor agonist, affects colorectal carcinogenesis. METHODS Naltrexone, an opioid receptor antagonist, was injected intraperitoneally every second day for 2 weeks, at the dose of 1 mg/kg in healthy Balb/C mice to induce changes in ORs expression. CRC was induced by a single intraperitoneal injection of azoxymethane (AOM) and the addition of dextran sodium sulfate (DSS) into drinking water in three-week cycles. The development of CRC was assessed using macro- and microscopic scoring and molecular analysis (RT qPCR, ELISA) after 14 weeks. RESULTS Naltrexone significantly increased the mRNA expression of Oprm1, Oprd1, and Oprk1 in the mouse colon and in the brain (non-significantly). The pretreatment of mice with naltrexone aggravated the course of CRC (as indicated by tumor area, colon thickness, and spleen weight). The level of circulatory adiponectin was lowered in mice with CRC and increased in the colon as compared with healthy mice. The β-endorphin level was increased in the plasma of mice with CRC and decreased in the colon as compared to healthy mice. AdipoRon, AdipoR1 agonist, worsened the CRC development, and pretreatment with naltrexone enhanced this negative effect in mice. CRC did not affect the expression of the Adipor1 gene, but the Adipor1 level was increased in mice pretreated with naltrexone (AOM/DSS and healthy mice). AdipoRon did not influence the expression of opioid receptors at the mRNA level in the colon of mice with CRC. The mRNA expression of Ptgs2, Il6, Nos2, Il1b, Il18, Gsdmd, and Rela was increased in mice with CRC as compared to the healthy colon. AdipoRon significantly decreased mRNA expression of Ptgs2, Il6, Il1b, and Il18 as compared to CRC mice. CONCLUSION EOS and adiponectin-related signaling may play a role in the pathogenesis of CRC and these systems may present some additivity during carcinogenesis.
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Affiliation(s)
- Agata Szymaszkiewicz
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Mikołaj Mierzejewski
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Emilia Januszkiewicz
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Weronika Machelak
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Marcin Talar
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Jakub Włodarczyk
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Mikołaj Świerczyński
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Radzisław Kordek
- Department of Pathology, Faculty of Medicine, Medical University of Łódź, Łódź, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland
| | - Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Łódź, Molecolab, Mazowiecka 5, 92-215, Łódź, Poland.
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13
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Sarabi PZ, Moradi M, Bagheri M, Khalili MR, Moradifard S, Jamialahmadi T, Ghasemi F, Sahebkar A. A Contemporary Review on the Critical Role of Nonsteroidal Anti-inflammatory Agents in Colorectal Cancer Therapy. Anticancer Agents Med Chem 2024; 24:559-570. [PMID: 38275052 DOI: 10.2174/0118715206271583231206052403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 01/27/2024]
Abstract
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are widely recognized as effective pain relievers and function by inhibiting the cyclooxygenase enzyme (COXs). Moreover, they have been found to participate in various cellular processes through different signaling pathways, such as WNT, MAPK, NF-κB, and PI3K/AKT/mTOR. This makes them potential candidates for chemoprevention of several malignancies, particularly colorectal cancer (CRC). However, the use of NSAIDs in cancer prevention and treatment is a complex issue due to their adverse effects and gastrointestinal toxicity. Therefore, it is crucial to explore combination therapies that can minimize side effects while maximizing synergistic effects with other agents and to evaluate the success rate of such approaches in both pre-clinical and clinical studies. In this review, we aim to provide an overview of the effects of NSAIDs in the prevention and treatment of CRC. We will focus on elucidating the possible mechanisms of action of these drugs, the signaling pathways involved in CRC, and the potential synergistic effects when combined with other therapeutic agents.
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Affiliation(s)
- Parisa Zia Sarabi
- Laboratorio de Psicobiología, Campus Santiago Ramón y Cajal, University of Sevilla, 41018, Sevilla, Spain
| | - Mohammad Moradi
- Department of Biotechnology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Malihe Bagheri
- Department of Biotechnology and Molecular Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Mohammad Reza Khalili
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Next to Milad Tower, Tehran, Iran
| | - Shahrzad Moradifard
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Next to Milad Tower, Tehran, Iran
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Ghasemi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Next to Milad Tower, Tehran, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Fen-Xu, Jiang LH, Chen-Fu, Feng WW, Zhou CJ. CRD-BP as a Tumor Marker of Colorectal Cancer. Anticancer Agents Med Chem 2024; 24:169-176. [PMID: 37990428 DOI: 10.2174/0118715206256546231108095912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 11/23/2023]
Abstract
The National Cancer Center published a comparative report on cancer data between China and the United States in the Chinese Medical Journal, which shows that colorectal cancer (CRC) ranks second in China and fourth in the United States. It is worth noting that since 2000, the case fatality rate of CRC in China has skyrocketed, while the United States has gradually declined. Finding tumor markers with high sensitivity and specificity is our primary goal to reduce the case fatality rate of CRC. Studies have shown that CRD-BP (Insulin-like growth factor 2 mRNA-binding protein 1) can affect a variety of signaling pathways, such as Wnt.nuclear factor KB (NF-κB), and Hedgehog, and has good biological effects as a therapeutic target for CRC. CRD-BP is expected to become a tumor marker with high sensitivity and specificity of CRC. This paper reviews the research on CRD-BP as a tumor marker of CRC.
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Affiliation(s)
- Fen-Xu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Liang-Hong Jiang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Chen-Fu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Wei-Wei Feng
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
| | - Chang-Jiang Zhou
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Liaoning Command, Liaoning 116000, Liaoning Province, China
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15
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Lv X, Zheng W, Geng S, Cui Y, Tao Y, Xu T. circCBL and its host gene CBL collaboratively enhance the antiviral immunity and antibacterial immunity by targeting MITA in fish. J Virol 2023; 97:e0104623. [PMID: 37800946 PMCID: PMC10617576 DOI: 10.1128/jvi.01046-23] [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: 07/13/2023] [Accepted: 08/21/2023] [Indexed: 10/07/2023] Open
Abstract
IMPORTANCE Increasing evidence indicates that circular RNAs exert crucial functions in regulating gene expression in mammals. However, the function of circRNAs in lower vertebrates still needs further exploration. Our research results demonstrated that circRNA, namely circCBL, is involved in modulating antiviral and antibacterial immune responses in lower vertebrates. In addition, our study also found that circCBL can serve as a competing endogenous RNA to facilitate MITA expression, thereby modulating MITA-mediated innate immunity. Further research has proved that the host gene CBL also promotes the expression of MITA, enhancing antiviral and antibacterial immune responses. Our study not only elucidated the underlying biological mechanism of the circRNA-miRNA-mRNA axis in the innate immune response of lower vertebrates but also unveiled the synergistic antibacterial and antiviral mechanisms between circRNA and its host gene in lower vertebrates.
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Affiliation(s)
- Xing Lv
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Weiwei Zheng
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Shang Geng
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Yanqiu Cui
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Yaqi Tao
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Tianjun Xu
- Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
- Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
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16
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Cherkasova V, Ilnytskyy Y, Kovalchuk O, Kovalchuk I. Transcriptome Analysis of Cisplatin, Cannabidiol, and Intermittent Serum Starvation Alone and in Various Combinations on Colorectal Cancer Cells. Int J Mol Sci 2023; 24:14743. [PMID: 37834191 PMCID: PMC10572413 DOI: 10.3390/ijms241914743] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Platinum-derived chemotherapy medications are often combined with other conventional therapies for treating different tumors, including colorectal cancer. However, the development of drug resistance and multiple adverse effects remain common in clinical settings. Thus, there is a necessity to find novel treatments and drug combinations that could effectively target colorectal cancer cells and lower the probability of disease relapse. To find potential synergistic interaction, we designed multiple different combinations between cisplatin, cannabidiol, and intermittent serum starvation on colorectal cancer cell lines. Based on the cell viability assay, we found that combinations between cannabidiol and intermittent serum starvation, cisplatin and intermittent serum starvation, as well as cisplatin, cannabidiol, and intermittent serum starvation can work in a synergistic fashion on different colorectal cancer cell lines. Furthermore, we analyzed differentially expressed genes and affected pathways in colorectal cancer cell lines to understand further the potential molecular mechanisms behind the treatments and their interactions. We found that synergistic interaction between cannabidiol and intermittent serum starvation can be related to changes in the transcription of genes responsible for cell metabolism and cancer's stress pathways. Moreover, when we added cisplatin to the treatments, there was a strong enrichment of genes taking part in G2/M cell cycle arrest and apoptosis.
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Affiliation(s)
| | | | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
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17
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Jiang Y, Zhang J, Shi C, Li X, Jiang Y, Mao R. NF- κB: a mediator that promotes or inhibits angiogenesis in human diseases? Expert Rev Mol Med 2023; 25:e25. [PMID: 37503730 DOI: 10.1017/erm.2023.20] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
The nuclear factor of κ-light chain of enhancer-activated B cells (NF-κB) signaling pathway, which is conserved in invertebrates, plays a significant role in human diseases such as inflammation-related diseases and carcinogenesis. Angiogenesis refers to the growth of new capillary vessels derived from already existing capillaries and postcapillary venules. Maintaining normal angiogenesis and effective vascular function is a prerequisite for the stability of organ tissue function, and abnormal angiogenesis often leads to a variety of diseases. It has been suggested that NK-κB signalling molecules under pathological conditions play an important role in vascular differentiation, proliferation, apoptosis and tumourigenesis by regulating the transcription of multiple target genes. Many NF-κB inhibitors are being tested in clinical trials for cancer treatment and their effect on angiogenesis is summarised. In this review, we will summarise the role of NF-κB signalling in various neovascular diseases, especially in tumours, and explore whether NF-κB can be used as an attack target or activation medium to inhibit tumour angiogenesis.
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Affiliation(s)
- Yijing Jiang
- Department of Pathophysiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu, People's Republic of China
| | - Jie Zhang
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, 30Tongyang North Road, Pingchao Town, Nantong 226361, Jiangsu, People's Republic of China
| | - Conglin Shi
- Department of Pathogenic Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu, People's Republic of China
| | - Xingjuan Li
- Department of Pathophysiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu, People's Republic of China
| | - Yongying Jiang
- Department of Pathophysiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu, People's Republic of China
| | - Renfang Mao
- Department of Pathophysiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu, People's Republic of China
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18
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Li M, Gao Z, Wang S, Zhao Y, Xie H. miR‑27a‑3p upregulation by p65 facilitates cervical tumorigenesis by increasing TAB3 expression and is involved in the positive feedback loop of NF‑κB signaling. Oncol Rep 2023; 50:132. [PMID: 37203408 PMCID: PMC10236263 DOI: 10.3892/or.2023.8569] [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: 01/18/2023] [Accepted: 04/04/2023] [Indexed: 05/20/2023] Open
Abstract
An altered microRNA (miRNA/miR)‑27a‑3p expression has been identified in cervical cancer, while the exact regulatory mechanisms responsible for the dysregulation of miR‑27a‑3p remain to be fully elucidated. In the present study, a NF‑κB/p65 binding site was identified upstream of the miR‑23a/27a/24‑2 cluster and p65 binding enhanced the transcription of pri‑miR‑23a/27a/24‑2, as well as the expression levels of mature miRNAs, including miR‑27a‑3p in HeLa cells. Mechanistically, using bioinformatics analyses and experimental validation, TGF‑β activated kinase 1 binding protein 3 (TAB3) was identified as a direct target of miR‑27a‑3p. By binding to the 3'UTR of TAB3, miR‑27a‑3p significantly enhanced TAB3 expression. Functionally, it was found that the overexpression of miR‑27a‑3p and TAB3 promoted the malignant potential of cervical cancer cells, as evaluated using cell growth, migration and invasion assays, and specific cell marker determinations in the epithelial mesenchymal transition progression, and vice versa. Further rescue experiments revealed that the enhanced malignant effects induced by miR‑27a‑3p were mediated via its upregulation of TAB3 expression. Moreover, miR‑27a‑3p and TAB3 also activated the NF‑κB signaling pathway and formed a positive feedback regulatory loop composing of p65/miR‑27a‑3p/TAB3/NF‑κB. On the whole, the findings presented herein may provide novel insight into the underlying cervical tumorigenesis and novel biomarker identification for clinical applications.
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Affiliation(s)
- Min Li
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Zixuan Gao
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Shuo Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise and Health, Tianjin University of Sports, Tianjin 301617, P.R. China
| | - Yungang Zhao
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise and Health, Tianjin University of Sports, Tianjin 301617, P.R. China
| | - Hong Xie
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China
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19
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Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther 2023; 8:198. [PMID: 37169756 PMCID: PMC10175505 DOI: 10.1038/s41392-023-01460-1] [Citation(s) in RCA: 436] [Impact Index Per Article: 218.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/20/2023] [Accepted: 04/20/2023] [Indexed: 05/13/2023] Open
Abstract
Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.
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Affiliation(s)
- Zhen-Ling Liu
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Huan-Huan Chen
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Li Zheng
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Ping Sun
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
| | - Lei Shi
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
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20
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α-Hederin Saponin Augments the Chemopreventive Effect of Cisplatin against Ehrlich Tumors and Bioinformatic Approach Identifying the Role of SDF1/CXCR4/p-AKT-1/NFκB Signaling. Pharmaceuticals (Basel) 2023; 16:ph16030405. [PMID: 36986504 PMCID: PMC10056433 DOI: 10.3390/ph16030405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/10/2023] Open
Abstract
Stromal cell-derived factor-1 (SDF1) and its C-X-C chemokine receptor type 4 receptor (CXCR4) are significant mediators for cancer cells’ proliferation, and we studied their expression in Ehrlich solid tumors (ESTs) grown in mice. α-Hederin is a pentacyclic triterpenoid saponin found in Hedera or Nigella species with biological activity that involves suppression of growth of breast cancer cell lines. The aim of this study was to explore the chemopreventive activity of α-hederin with/without cisplatin; this was achieved by measuring the reduction in tumor masses and the downregulation in SDF1/CXCR4/pAKT signaling proteins and nuclear factor kappa B (NFκB). Ehrlich carcinoma cells were injected in four groups of Swiss albino female mice (Group1: EST control group, Group2: EST + α-hederin group, Group3: EST + cisplatin group, and Group4: EST+α-hederin/cisplatin treated group). Tumors were dissected and weighed, one EST was processed for histopathological staining with hematoxylin and eosin (HE), and the second MC was frozen and processed for estimation of signaling proteins. Computational analysis for these target proteins interactions showed direct-ordered interactions. The dissected solid tumors revealed decreases in tumor masses (~21%) and diminished viable tumor regions with significant necrotic surrounds, particularly with the combination regimens. Immunohistochemistry showed reductions (~50%) in intratumoral NFκβ in the mouse group that received the combination therapy. The combination treatment lowered the SDF1/CXCR4/p-AKT proteins in ESTs compared to the control. In conclusion, α-hederin augmented the chemotherapeutic potential of cisplatin against ESTs; this effect was at least partly mediated through suppressing the chemokine SDF1/CXCR4/p-AKT/NFκB signaling. Further studies are recommended to verify the chemotherapeutic potential of α-hederin in other breast cancer models.
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21
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Merhi M, Ahmad F, Taib N, Inchakalody V, Uddin S, Shablak A, Dermime S. The complex network of transcription factors, immune checkpoint inhibitors and stemness features in colorectal cancer: A recent update. Semin Cancer Biol 2023; 89:1-17. [PMID: 36621515 DOI: 10.1016/j.semcancer.2023.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/19/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Cancer immunity is regulated by several mechanisms that include co-stimulatory and/or co-inhibitory molecules known as immune checkpoints expressed by the immune cells. In colorectal cancer (CRC), CTLA-4, LAG3, TIM-3 and PD-1 are the major co-inhibitory checkpoints involved in tumor development and progression. On the other hand, the deregulation of transcription factors and cancer stem cells activity plays a major role in the development of drug resistance and in the spread of metastatic disease in CRC. In this review, we describe how the modulation of such transcription factors affects the response of CRC to therapies. We also focus on the role of cancer stem cells in tumor metastasis and chemoresistance and discuss both preclinical and clinical approaches for targeting stem cells to prevent their tumorigenic effect. Finally, we provide an update on the clinical applications of immune checkpoint inhibitors in CRC and discuss the regulatory effects of transcription factors on the expression of the immune inhibitory checkpoints with specific focus on the PD-1 and PD-L1 molecules.
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Affiliation(s)
- Maysaloun Merhi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Fareed Ahmad
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Nassiba Taib
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Varghese Inchakalody
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Alaaeldin Shablak
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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22
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MCPIP1 Suppresses the NF-κB Signaling Pathway Through Negative Regulation of K63-Linked Ubiquitylation of TRAF6 in Colorectal Cancer. Cancer Gene Ther 2023; 30:96-107. [PMID: 36076064 DOI: 10.1038/s41417-022-00528-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/10/2022] [Accepted: 08/24/2022] [Indexed: 01/19/2023]
Abstract
The abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is an important precipitating factor for the inception and development of colorectal cancer (CRC), one of the most common tumors worldwide. As a pro-apoptotic transcription factor, monocyte chemotactic protein-induced protein 1 (MCPIP1) has been closely associated with many tumor types. In the present study, the expression of MCPIP1 was firstly discovered reduced in CRC tissues and correlated with poor patient prognosis. The decreased expression was caused by promoter hypermethylation. Overexpressed MCPIP1 was found to inhibit the proliferative and migratory abilities of CRC cells, whereas knockdown of MCPIP1 produced the opposite result. The subsequent investigation demonstrated that MCPIP1 exerted its "anti-cancer" effect by suppression of the NF-κB signaling pathway through negative regulation of K63-linked ubiquitylation of TNF receptor associated factor 6 (TRAF6). Therefore, our results indicate a prognostic marker for CRC and a theoretical basis for MCPIP1 as a treatment.
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23
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Abstract
The etiology of colorectal cancer (CRC) is influenced by bacterial communities that colonize the gastrointestinal tract. These microorganisms derive essential nutrients from indigestible dietary or host-derived compounds and activate molecular signaling pathways necessary for normal tissue and immune function. Associative and mechanistic studies have identified bacterial species whose presence may increase CRC risk, including notable examples such as Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis, and pks+ E. coli. In recent years this work has expanded in scope to include aspects of host mutational status, intra-tumoral microbial heterogeneity, transient infection, and the cumulative influence of multiple carcinogenic bacteria after sequential or co-colonization. In this review, we will provide an updated overview of how host-bacteria interactions influence CRC development, how this knowledge may be utilized to diagnose or prevent CRC, and how the gut microbiome influences CRC treatment efficacy.
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Affiliation(s)
- Michael W. Dougherty
- Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Christian Jobin
- Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
- Department of Infectious Diseases and Immunology, University of Florida College of Medicine, Gainesville, FL, USA
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA
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24
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Cao M, Wang Y, Lu G, Qi H, Li P, Dai X, Lu J. Classical Angiogenic Signaling Pathways and Novel Anti-Angiogenic Strategies for Colorectal Cancer. Curr Issues Mol Biol 2022; 44:4447-4471. [PMID: 36286020 PMCID: PMC9601273 DOI: 10.3390/cimb44100305] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/17/2022] [Accepted: 09/21/2022] [Indexed: 11/17/2022] Open
Abstract
Although productive progress has been made in colorectal cancer (CRC) researchs, CRC is the second most frequent type of malignancy and the major cause of cancer-related death among gastrointestinal cancers. As angiogenesis constitutes an important point in the control of CRC progression and metastasis, understanding the key signaling pathways that regulate CRC angiogenesis is critical in elucidating ways to inhibit CRC. Herein, we comprehensively summarized the angiogenesis-related pathways of CRC, including vascular endothelial growth factor (VEGF), nuclear factor-kappa B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Wingless and int-1 (Wnt), and Notch signaling pathways. We divided the factors influencing the specific pathway into promoters and inhibitors. Among these, some drugs or natural compounds that have antiangiogenic effects were emphasized. Furthermore, the interactions of these pathways in angiogenesis were discussed. The current review provides a comprehensive overview of the key signaling pathways that are involved in the angiogenesis of CRC and contributes to the new anti-angiogenic strategies for CRC.
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Affiliation(s)
- Mengyuan Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yunmeng Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Guige Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Haoran Qi
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Peiyu Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xiaoshuo Dai
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
- Correspondence:
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25
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Lyu S, Zhang X, Tu Z, Zhou H, Ke X, Qu Y. GPR108 is required for gambogic acid inhibiting NF-κB signaling in cancer. Pharmacol Res 2022; 182:106279. [PMID: 35659621 DOI: 10.1016/j.phrs.2022.106279] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/14/2022] [Accepted: 05/26/2022] [Indexed: 10/18/2022]
Abstract
GPCRs are the most potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based anti-cancer drug is not fully investigated. Herein, we identified GPR108, a GPCR protein described in innate immune system, is a potential therapeutic target of cancer. Depletion of GPR108 dramatically inhibited the survival of various cancers. Notably, TNFα activation of NF-κB was totally impaired after GPR108 knockout. We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. Importantly, GA engaged with GPR108 and promoted its degradation, knockout of GPR108 remarkably blocked GA inhibition of NF-κB signaling. Furthermore, in vitro and in vivo assays demonstrated that GA was dependent on GPR108 to exert anti-cancer activity. Overall, our findings supported GPR108 as a promising therapeutic target of cancer, and provided a small molecule inhibitor GA directly and selectively targeting GPR108 for cancer therapy.
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Affiliation(s)
- Song Lyu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xue Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhenzhen Tu
- Department of Biochemistry and Molecular Biology, Anhui Medical University, No. 69 Mei Shan Road, Hefei, China
| | - Haisheng Zhou
- Department of Biochemistry and Molecular Biology, Anhui Medical University, No. 69 Mei Shan Road, Hefei, China
| | - Xisong Ke
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yi Qu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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26
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Ye Z, Yang Y, Wei Y, Li L, Wang X, Zhang J. PCDH1 promotes progression of pancreatic ductal adenocarcinoma via activation of NF-κB signalling by interacting with KPNB1. Cell Death Dis 2022; 13:633. [PMID: 35864095 PMCID: PMC9304345 DOI: 10.1038/s41419-022-05087-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 07/07/2022] [Accepted: 07/07/2022] [Indexed: 01/21/2023]
Abstract
Uncontrolled growth, distant metastasis and chemoresistance are critical characteristics of pancreatic ductal adenocarcinoma (PDAC), and they result in high mortality; however, the mechanisms triggering these effects have not been fully investigated. In this study, we analysed a dataset in the Cancer Genome Atlas (TCGA) and identified PCDH1, a rarely studied transmembrane protein, as a novel prognostic marker in PDAC patients. We demonstrated that PCDH1 expression was upregulated in PDAC tissues, and its expression levels were associated with the depth of tumour invasion and lymph node metastasis. Patients with high PCDH1 levels showed poor overall survival (OS). We also investigated the biological significance of PCDH1 in PDAC cell growth, metastasis, and side population (SP) phenotype acquisition and explored the internal molecular mechanisms of PCDH1 action. Our results demonstrated that PCDH1 enhanced p65 nuclear localization by interacting with KPNB1, a well-characterized nuclear transporter, thereby activating the NF-κB signalling pathway and increasing its functional effects during PDAC progression. Hence, our results indicate that PCDH1 can be used as a negative prognostic marker and may be a potential therapeutic target for PDAC patients.
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Affiliation(s)
- Zhihua Ye
- Department of Medical Oncology Center, Zhongshan City People's Hospital, 528403, Zhongshan City, Guangdong Province, P. R. China
| | - Yingyu Yang
- Department of Medical Oncology Center, Zhongshan City People's Hospital, 528403, Zhongshan City, Guangdong Province, P. R. China
| | - Ying Wei
- Department of Medical Oncology Center, Zhongshan City People's Hospital, 528403, Zhongshan City, Guangdong Province, P. R. China
| | - Lamei Li
- Department of Medical Oncology Center, Zhongshan City People's Hospital, 528403, Zhongshan City, Guangdong Province, P. R. China
| | - Xinyi Wang
- Department of Medical Oncology Center, Zhongshan City People's Hospital, 528403, Zhongshan City, Guangdong Province, P. R. China
| | - Junkai Zhang
- Department of Medical Oncology Center, Zhongshan City People's Hospital, 528403, Zhongshan City, Guangdong Province, P. R. China.
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27
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Di Vito Nolfi M, Vecchiotti D, Flati I, Verzella D, Di Padova M, Alesse E, Capece D, Zazzeroni F. EV-Mediated Chemoresistance in the Tumor Microenvironment: Is NF-κB a Player? Front Oncol 2022; 12:933922. [PMID: 35814425 PMCID: PMC9257640 DOI: 10.3389/fonc.2022.933922] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
Drug resistance is a major impediment to patient survival and remains the primary cause of unsuccessful cancer therapy. Drug resistance occurs in many tumors and is frequently induced by chemotherapy which triggers a defensive response both in cancerous and cancer-associated cells that constitute the tumor microenvironment (TME). Cell to cell communication within the TME is often mediated by extracellular vesicles (EVs) which carry specific tumor-promoting factors able to activate survival pathways and immune escape mechanisms, thus sustaining tumor progression and therapy resistance. NF-κB has been recognized as a crucial player in this context. NF-κB activation is involved in EVs release and EVs, in turn, can trigger NF-κB pathway activation in specific contexts, based on secreting cytotype and their specific delivered cargo. In this review, we discuss the role of NF-κB/EVs interplay that sustain chemoresistance in the TME by focusing on the molecular mechanisms that underlie inflammation, EVs release, and acquired drug resistance.
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Affiliation(s)
| | | | | | | | | | | | - Daria Capece
- *Correspondence: Francesca Zazzeroni, ; Daria Capece,
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28
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Zhang M, Tao Z, Gao L, Chen F, Ye Y, Xu S, Huang W, Li X. Toosendanin inhibits colorectal cancer cell growth through the Hedgehog pathway by targeting Shh. Drug Dev Res 2022; 83:1201-1211. [PMID: 35656621 DOI: 10.1002/ddr.21951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/26/2022] [Accepted: 05/09/2022] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. This complex and often fatal disease has a high mortality rate. The Hedgehog (Hh) signaling pathway is crucial in CRC. Many studies have indicated that Shh is overexpressed in cancer stem cells (CSCs), and shh overexpression is positively correlated with CRC tumorigenesis. New drugs that kill CRC cells through the Hh pathway are needed. Toosendanin (TSN), a natural triterpenoid saponin extracted from the bark or fruit of Melia toosendan Sieb. et Zucc, can inhibit various tumors. Here, we investigated the effects of TSN in CRC and explored the possible targets and mechanisms. Shh-Light Ⅱ cells were treated with TSN and tested by dual luciferase reporter assays to determine the relationship with the Hh pathway. Cell Counting Kit-8 (CCK-8) assays were used to test the inhibitory effects of TSN on CRC cells. The expression of Hh components after TSN treatment was detected using western blots and quantitative reverse transcription polymerase chain reaction. Cellular thermal shift assays confirmed the targets of TSN. The same effects of TSN on xenograft tumor growth were investigated in vivo. The average weight, volume of the finally resected tumor, and the expression of Shh in the TSN-treated groups were significantly lower than those of the control group. This result strongly suggested that TSN administration inhibited CRC growth in vivo. Our research preliminarily demonstrated that the target of TSN was Shh and that TSN inhibits CRC cell growth by inhibiting the Hh pathway, identifying a new anticancer molecular mechanism of TSN in CRC.
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Affiliation(s)
- Meng Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhongyi Tao
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lijuan Gao
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Fengyang Chen
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yiping Ye
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Shifang Xu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Wenkang Huang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiaoyu Li
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
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29
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Li X, Gao S, Zhang Y, Xin M, Zuo C, Yan N, Xia Q, Zhang M. Dihydroartemisinin Inhibits Laser-Induced Choroidal Neovascularization in a Mouse Model of Neovascular AMD. Front Pharmacol 2022; 13:838263. [PMID: 35250585 PMCID: PMC8894668 DOI: 10.3389/fphar.2022.838263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose: Choroidal neovascularization (CNV) is the main pathogenic process and a leading cause of severe vision loss in neovascular age-related macular degeneration (AMD). We investigated the antiangiogenic efficacy of dihydroartemisinin (DHA) in an experimental laser-induced CNV mouse model. Methods: After fluorescein angiography confirmed that CNV was induced by laser photocoagulation in C57BL/6J mice, DHA or vehicle was given by intragastric administration once a day. On day 6 and day 12, fluorescein angiography, optic coherence tomography, and flat-mounting analysis were performed to grade CNV leakage, measure CNV thickness and evaluate CNV areas, respectively. Immunofluorescence staining and Western blot analysis were performed to evaluate the expression of NF-κB, VEGF, and VEGFR2. To confirm the safety of intragastric DHA application, changes in retinal morphology and neural cell apoptosis were tested by histopathological examination and TUNEL assay, and retinal function was determined by electroretinogram (ERG). Results: Intragastric administration of DHA significantly suppressed CNV leakage and CNV formation in both thickness and area. Immunofluorescence showed that DHA suppressed VEGFR2 and NF-κB p65 expression in laser-induced lesions. Compared to the normal group, the protein expression of VEGF, VGFER2, NF-κB p65, and NF-κB1 p50 increased significantly in the vehicle group after laser photocoagulation, while it was profoundly inhibited by DHA treatment. In addition, histopathological examination, TUNEL analysis, and ERG test showed no obvious evidence of retinal toxicity caused by DHA. Conclusion: Systemic administration of DHA can effectively inhibit laser-induced CNV formation in mice, which might be due to the suppression of the classic NF-κB signaling pathway and downregulation of VEGFR2 and VEGF expression. The current results suggest that DHA could be a natural potential alternative therapeutic strategy for neovascular AMD.
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Affiliation(s)
- Xun Li
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Science, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Sheng Gao
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Yun Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Mei Xin
- Department of Ophthalmology, Chengdu First People’s Hospital, Chengdu, China
| | - Cheng Zuo
- Department of Ophthalmology, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Naihong Yan
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Ophthalmology and Vision Science, West China Hospital, Sichuan University, Chengdu, China
| | - Qingjie Xia
- Laboratory of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Meixia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
- Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Meixia Zhang,
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30
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IKKα plays a major role in canonical NF-kB signalling in colorectal cells. Biochem J 2022; 479:305-325. [PMID: 35029639 PMCID: PMC8883499 DOI: 10.1042/bcj20210783] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 11/17/2022]
Abstract
Inhibitor of kappa B (IκB) kinase β (IKKβ) has long been viewed as the dominant IKK in the canonical nuclear factor-κB (NF-κB) signalling pathway, with IKKα being more important in non-canonical NF-κB activation. Here we have investigated the role of IKKα and IKKβ in canonical NF-κB activation in colorectal cells using CRISPR–Cas9 knock-out cell lines, siRNA and selective IKKβ inhibitors. IKKα and IKKβ were redundant for IκBα phosphorylation and turnover since loss of IKKα or IKKβ alone had little (SW620 cells) or no (HCT116 cells) effect. However, in HCT116 cells IKKα was the dominant IKK required for basal phosphorylation of p65 at S536, stimulated phosphorylation of p65 at S468, nuclear translocation of p65 and the NF-κB-dependent transcriptional response to both TNFα and IL-1α. In these cells, IKKβ was far less efficient at compensating for the loss of IKKα than IKKα was able to compensate for the loss of IKKβ. This was confirmed when siRNA was used to knock-down the non-targeted kinase in single KO cells. Critically, the selective IKKβ inhibitor BIX02514 confirmed these observations in WT cells and similar results were seen in SW620 cells. Notably, whilst IKKα loss strongly inhibited TNFα-dependent p65 nuclear translocation, IKKα and IKKβ contributed equally to c-Rel nuclear translocation indicating that different NF-κB subunits exhibit different dependencies on these IKKs. These results demonstrate a major role for IKKα in canonical NF-κB signalling in colorectal cells and may be relevant to efforts to design IKK inhibitors, which have focused largely on IKKβ to date.
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31
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Abumustafa W, Zamer BA, Khalil BA, Hamad M, Maghazachi AA, Muhammad JS. Protein arginine N-methyltransferase 5 in colorectal carcinoma: Insights into mechanisms of pathogenesis and therapeutic strategies. Biomed Pharmacother 2022; 145:112368. [PMID: 34794114 DOI: 10.1016/j.biopha.2021.112368] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
Protein arginine N-methyltransferase 5 (PRMT5) enzyme is one of the eight canonical PRMTs, classified as a type II PRMT, induces arginine monomethylation and symmetric dimethylation. PRMT5 is known to be overexpressed in multiple cancer types, including colorectal cancer (CRC), where its overexpression is associated with poor survival. Recent studies have shown that upregulation of PRMT5 induces tumor growth and metastasis in CRC. Moreover, various novel PRMT5 inhibitors tested on CRC cell lines showed promising anticancer effects. Also, it was suggested that PRMT5 could be a valid biomarker for CRC diagnosis and prognosis. Hence, a deeper understanding of PRMT5-mediated CRC carcinogenesis could provide new avenues towards developing a targeted therapy. In this study, we started with in silico analysis correlating PRMT5 expression in CRC patients as a prelude to further our investigation of its role in CRC. We then carried out a comprehensive review of the scientific literature that dealt with the role(s) of PRMT5 in CRC pathogenesis, diagnosis, and prognosis. Also, we have summarized key findings from in vitro research using various therapeutic agents and strategies directly targeting PRMT5 or disrupting its function. In conclusion, PRMT5 seems to play a significant role in the pathogenesis of CRC; therefore, its prognostic and therapeutic potential merits further investigation.
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Affiliation(s)
- Wafaa Abumustafa
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Batoul Abi Zamer
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Bariaa A Khalil
- Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Mawieh Hamad
- Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah, United Arab Emirates; Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A Maghazachi
- Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah, United Arab Emirates; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
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32
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Wang RQ, Zhao W, Yang HK, Dong JM, Lin WJ, He FZ, Cui M, Zhou ZL. Single-Cell RNA Sequencing Analysis of the Heterogeneity in Gene Regulatory Networks in Colorectal Cancer. Front Cell Dev Biol 2021; 9:765578. [PMID: 34917613 PMCID: PMC8669944 DOI: 10.3389/fcell.2021.765578] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/27/2021] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer (CRC) manifests as gastrointestinal tumors with high intratumoral heterogeneity. Recent studies have demonstrated that CRC may consist of tumor cells with different consensus molecular subtypes (CMS). The advancements in single-cell RNA sequencing have facilitated the development of gene regulatory networks to decode key regulators for specific cell types. Herein, we comprehensively analyzed the CMS of CRC patients by using single-cell RNA-sequencing data. CMS for all malignant cells were assigned using CMScaller. Gene set variation analysis showed pathway activity differences consistent with those reported in previous studies. Cell–cell communication analysis confirmed that CMS1 was more closely related to immune cells, and that monocytes and macrophages play dominant roles in the CRC tumor microenvironment. On the basis of the constructed gene regulation networks (GRNs) for each subtype, we identified that the critical transcription factor ERG is universally activated and upregulated in all CMS in comparison with normal cells, and that it performed diverse roles by regulating the expression of different downstream genes. In summary, molecular subtyping of single-cell RNA-sequencing data for colorectal cancer could elucidate the heterogeneity in gene regulatory networks and identify critical regulators of CRC.
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Affiliation(s)
- Rui-Qi Wang
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Wei Zhao
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Hai-Kui Yang
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Jia-Mei Dong
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Wei-Jie Lin
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Fa-Zhong He
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Min Cui
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Zhi-Ling Zhou
- Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
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33
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Ho TY, Mealiea D, Okamoto L, Stojdl DF, McCart JA. Deletion of immunomodulatory genes as a novel approach to oncolytic vaccinia virus development. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:85-97. [PMID: 34514091 PMCID: PMC8411212 DOI: 10.1016/j.omto.2021.05.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 05/12/2021] [Indexed: 11/30/2022]
Abstract
Vaccinia virus (VV) has emerged as a promising platform for oncolytic virotherapy. Many clinical VV candidates, such as the double-deleted VV, vvDD, are engineered with deletions that enhance viral tumor selectivity based on cellular proliferation rates. An alternative approach is to exploit the dampened interferon-based innate immune responses of tumor cells by deleting one of the many VV immunomodulatory genes expressed to dismantle the antiviral response. We hypothesized that such a VV mutant would be attenuated in non-tumor cells but retain the ability to effectively propagate in and kill tumor cells, yielding a tumor-selective oncolytic VV with significant anti-tumor potency. In this study, we demonstrated that VVs with a deletion in one of several VV immunomodulatory genes (N1L, K1L, K3L, A46R, or A52R) have similar or improved in vitro replication, spread, and cytotoxicity in colon and ovarian cancer cells compared to vvDD. These deletion mutants are tumor selective, and the best performing candidates (ΔK1L, ΔA46R, and ΔA52R VV) are associated with significant improvement in survival, as well as immunomodulation, within the tumor environment. Overall, we show that exploiting the diminished antiviral responses in tumors serves as an effective strategy for generating tumor-selective and potent oncolytic VVs, with important implications in future oncolytic virus (OV) design.
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Affiliation(s)
- Tiffany Y Ho
- Toronto General Hospital Research Institute, University Health Network, 280 Elizabeth Street, Toronto, ON M5G 2C4, Canada
| | - David Mealiea
- Toronto General Hospital Research Institute, University Health Network, 280 Elizabeth Street, Toronto, ON M5G 2C4, Canada.,Department of Surgery, University of Toronto, Stewart Building, 149 College Street, Toronto, ON M5T 1P5, Canada
| | - Lili Okamoto
- Toronto General Hospital Research Institute, University Health Network, 280 Elizabeth Street, Toronto, ON M5G 2C4, Canada
| | - David F Stojdl
- Department of Biology, Microbiology, and Immunology, Children's Hospital of Eastern Ontario (CHEO) Research Institute, 401 Smyth Road, Ottawa ON K1H 5B2, Canada
| | - J Andrea McCart
- Toronto General Hospital Research Institute, University Health Network, 280 Elizabeth Street, Toronto, ON M5G 2C4, Canada.,Department of Surgery, University of Toronto, Stewart Building, 149 College Street, Toronto, ON M5T 1P5, Canada
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34
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Cherkasova V, Kovalchuk O, Kovalchuk I. Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer. Cancers (Basel) 2021; 13:4353. [PMID: 34503163 PMCID: PMC8430689 DOI: 10.3390/cancers13174353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 08/25/2021] [Indexed: 01/02/2023] Open
Abstract
Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world's disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
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Affiliation(s)
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
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Zhuang QS, Sun XB, Chong QY, Banerjee A, Zhang M, Wu ZS, Zhu T, Pandey V, Lobie PE. ARTEMIN Promotes Oncogenicity and Resistance to 5-Fluorouracil in Colorectal Carcinoma by p44/42 MAPK Dependent Expression of CDH2. Front Oncol 2021; 11:712348. [PMID: 34422665 PMCID: PMC8377398 DOI: 10.3389/fonc.2021.712348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/07/2021] [Indexed: 12/12/2022] Open
Abstract
ARTEMIN (ARTN), one of the glial-cell derived neurotrophic factor family of ligands, has been reported to be associated with a number of human malignancies. In this study, the enhanced expression of ARTN in colorectal carcinoma (CRC) was observed; the expression of ARTN positively correlated with lymph node metastases and advanced tumor stages and predicted poor prognosis. Forced expression of ARTN in CRC cells enhanced oncogenic behavior, mesenchymal phenotype, stem cell-like properties and tumor growth and metastasis in a xenograft model. These functions were conversely inhibited by depletion of endogenous ARTN. Forced expression of ARTN reduced the sensitivity of CRC cells to 5-FU treatment; and 5-FU resistant CRC cells harbored enhanced expression of ARTN. The oncogenic functions of ARTN were demonstrated to be mediated by p44/42 MAP kinase dependent expression of CDH2 (CADHERIN 2, also known as N-CADHERIN). Inhibition of p44/42 MAP kinase activity or siRNA mediated depletion of endogenous CDH2 reduced the enhanced oncogenicity and chemoresistance consequent to forced expression of ARTN induced cell functions; and forced expression of CDH2 rescued the reduced mesenchymal properties and resistance to 5-FU after ARTN depletion. In conclusion, ARTN may be of prognostic and theranostic utility in CRC.
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Affiliation(s)
- Qiu-Shi Zhuang
- Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore, Singapore.,Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.,Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
| | - Xin-Bao Sun
- Department of Oncology of the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Qing-Yun Chong
- Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Arindam Banerjee
- Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore, Singapore.,Department of Chemical Engineering, Indian Institute of Technology, Kharagpur, India
| | - Min Zhang
- Department of Oncology of the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Zheng-Sheng Wu
- Department of Pathology, Anhui Medical University, Hefei, China
| | - Tao Zhu
- Department of Oncology of the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Vijay Pandey
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.,Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
| | - Peter E Lobie
- Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore, Singapore.,Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.,Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.,Shenzhen Bay Laboratory, Shenzhen, China
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36
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Feng Z, Duan Z, Shi G, Wang Q, Zhou J, Chen Y. Pharmacological inhibition of IRAK1 attenuates colitis-induced tumorigenesis in mice by inhibiting the inflammatory response and epithelial-mesenchymal transition. J Biochem Mol Toxicol 2021; 35:e22838. [PMID: 34273909 DOI: 10.1002/jbt.22838] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 05/03/2021] [Accepted: 06/25/2021] [Indexed: 12/28/2022]
Abstract
Colorectal cancer (CRC) is the third most common type of cancer. Here, we studied the inhibitory effect of IRAK1 and IRAK4 as a preventive strategy using a colitis-induced tumorigenesis mouse model. CRC clinical data were obtained from the Gene Expression Omnibus (GEO). An experimental inflammation-dependent CRC model was induced by treatment with azoxymethane (AOM) and then dextran sodium sulfate (DSS) in C57BL/6 mice. Mice were administered an IRAK1/4 inhibitor by intraperitoneal injection at 3 mg/kg twice each week for 9 weeks. The IRAK1/4 inhibitor attenuated histological changes and prevented tumor growth. Tumor-associated proteins, including p65 and Ki-67, were downregulated by the IRAK1/4 inhibitor in AOM/DSS-treated mice. Additionally, IRAK1/4 inhibitor administration effectively decreased the expression of inflammatory cytokines. Furthermore, we observed that IRAK1/4 inhibitor treatment attenuated colitis-induced tumorigenesis by inhibiting epithelial-mesenchymal transition. These observations indicate that inhibition of IRAK1 and IRAK4 may suppress experimental colitis-induced tumorigenesis by inhibiting inflammatory responses and epithelial-mesenchymal transition.
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Affiliation(s)
- Zeyu Feng
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhenglan Duan
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Guoping Shi
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qiong Wang
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jinyong Zhou
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yugen Chen
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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Mao J, Wang M, Ni L, Gong W, Jiang X, Zhang Q, Zhang M, Wen D, Chen J. Local NF-κB Activation Promotes Parathyroid Hormone Synthesis and Secretion in Uremic Patients. Endocrinology 2021; 162:6257872. [PMID: 33912936 DOI: 10.1210/endocr/bqab084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Indexed: 12/19/2022]
Abstract
Secondary hyperparathyroidism (SHPT) in uremic patients is characterized by parathyroid gland (PTG) hyperplasia and parathyroid hormone (PTH) elevation. Previously, we demonstrated that NF-κB activation contributed to parathyroid cell proliferation in rats with chronic kidney disease. Although vitamin D inhibits inflammation and ameliorates SHPT, the contribution of vitamin D deficiency to SHPT via local NF-κB activation remains to be clarified. PTGs collected from 10 uremic patients with advanced SHPT were used to test the expressions of vitamin D receptor (VDR), NF-κB, and proliferating cell nuclear antigen (PCNA). Freshly excised PTG tissues were incubated for 24 hours in vitro with VDR activator (VDRA) calcitriol or NF-κB inhibitor pyrrolidine thiocarbamate (PDTC). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to investigate the regulation of PTH transcription by NF-κB. We found higher levels of activated NF-κB and lower expression of VDR in nodular hyperplastic PTGs than in diffuse hyperplasia. In cultured PTG tissues, treatment with VDRA or PDTC inhibited NF-κB activation and PCNA expression, and downregulated preproPTH mRNA and intact PTH levels. ChIP assays demonstrated the presence of NF-κB binding sites in PTH promoter. Furthermore, in luciferase reporter assays, addition of exogenous p65 significantly increased PTH luciferase activity by 2.4-fold (P < 0.01), while mutation of NF-κB binding site at position -908 of the PTH promoter suppressed p65-induced PTH reporter activity (P < 0.01). In summary, local NF-κB activation contributes to SHPT and mediates the transcriptional activation of PTH directly in uremic patients. Vitamin D deficiency may be involved in SHPT via the activation of NF-κB pathway.
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Affiliation(s)
- Jianping Mao
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Mengjing Wang
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Li Ni
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Wen Gong
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Xinxin Jiang
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Qian Zhang
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Minmin Zhang
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Donghai Wen
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Jing Chen
- Division of Nephrology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
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Qin Z, Yang Q, Liao R, Su B. The Association Between Dietary Inflammatory Index and Parathyroid Hormone in Adults With/Without Chronic Kidney Disease. Front Nutr 2021; 8:688369. [PMID: 34249998 PMCID: PMC8266995 DOI: 10.3389/fnut.2021.688369] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/01/2021] [Indexed: 02/05/2023] Open
Abstract
Aims: We aimed to assess the association between dietary inflammation index (DII) with parathyroid hormone (PTH) and hyperparathyroidism (HP) in adults with/without chronic kidney disease (CKD). Methods: Data were obtained from the 2003–2006 National Health and Nutrition Examination Survey (NHANES). The participants who were <18 years old, pregnant, or missing the data of DII, PTH, and CKD were excluded. DII was calculated based on a 24-h dietary recall interview for each participant. Weighted multivariable regression analysis and subgroup analysis were conducted to estimate the independent relationship between DII with PTH and the HP in the population with CKD/non-CKD. Results: A total of 7,679 participants were included with the median DII of −0.24 (−2.20 to 1.80) and a mean PTH level of 43.42 ± 23.21 pg/ml. The average PTH was 45.53 ± 26.63 pg/ml for the participants in the highest tertile group compared with 41.42 ± 19.74 pg/ml in the lowest tertile group (P < 0.0001). The rate of HP was 11.15% overall, while the rate in the highest DII tertile was 13.28 and 8.60% in the lowest DII tertile (P < 0.0001). The participants with CKD tended to have higher PTH levels compared with their counterparts (61.23 ± 45.62 vs. 41.80 ± 19.16 pg/ml, P < 0.0001). A positive association between DII scores and PTH was observed (β = 0.46, 95% CI: 0.25, 0.66, P ≤ 0.0001), and higher DII was associated with an increased risk of HP (OR = 1.05, 95% CI: 1.02, 1.08, P = 0.0023). The results from subgroup analysis indicated that this association was similar in the participants with different renal function, gender, age, BMI, hypertension, and diabetes statuses and could also be appropriate for the population with CKD. Conclusions: Higher consumption of a pro-inflammatory diet appeared to cause a higher PTH level and an increased risk of HP. Anti-inflammatory dietary management may be beneficial to reduce the risk of HP both in the population with and without CKD.
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Affiliation(s)
- Zheng Qin
- Department of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qinbo Yang
- Department of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoxi Liao
- Department of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Baihai Su
- Department of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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Cheng KJ, Mejia Mohammed EH, Khong TL, Mohd Zain S, Thavagnanam S, Ibrahim ZA. IL-1α and colorectal cancer pathogenesis: Enthralling candidate for anti-cancer therapy. Crit Rev Oncol Hematol 2021; 163:103398. [PMID: 34147647 DOI: 10.1016/j.critrevonc.2021.103398] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 01/04/2023] Open
Abstract
Inflammation has been well-established as a hallmark of colorectal cancer (CRC). Interleukin-1 alpha (IL-1α) is one of the primary inflammatory mediators driving the pathogenesis of inflammation-associated CRC. This systematic review presents the roles of IL-1α in the pathogenesis of the disease. Bibliographic databases PubMed, Science Direct, Scopus and Web of Science were systematically searched for articles that addresses the relationship between IL-1α and colorectal cancer. We highlighted various mechanisms by which IL-1α promotes the pathogenesis of CRC including enhancement of angiogenesis, metastasis, resistance to therapy, and inhibition of tumour suppressive genes. We also discussed the potential mechanisms by which IL-1α expression is induced or secreted in various studies. Beyond these, the systematic review also highlights several potential therapeutic strategies which should be further explored in the future; to target IL-1α and/or its associated pathways; paving our way in finding effective treatments for CRC patients.
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Affiliation(s)
- Kim Jun Cheng
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Tak Loon Khong
- Department of Surgery, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Shamsul Mohd Zain
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Surendran Thavagnanam
- Department of Paediatrics, Royal London Hospital, Whitechapel Rd, Whitechapel, E1 1FR London, United Kingdom
| | - Zaridatul Aini Ibrahim
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
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40
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Torreggiani E, Bononi I, Pietrobon S, Mazzoni E, Guerra G, Feo C, Martini F, Tognon M. Colorectal Carcinoma Affected Patients Are Significantly Poor Responders Against the Oncogenic JC Polyomavirus. Front Immunol 2021; 12:632129. [PMID: 34113338 PMCID: PMC8185217 DOI: 10.3389/fimmu.2021.632129] [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: 11/22/2020] [Accepted: 05/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Many investigations reported the association between human tumors and JCPyV, a polyomavirus with oncogenic potential. The association has been supported by studies that found JCPyV footprints in CRC and gliomas of different types. Indeed, JCPyV footprints including its nucleic acids and Tag oncoprotein have been revealed in CRC tissues. Methods Herein, sera from colorectal carcinoma (CRC) affected patients and healthy individuals (HS), employed as control, were analysed for immunoglobulin G (IgG) antibodies against specific JCPyV viral capsid protein 1 (VP1) antigens. The investigation was carried out employing an innovative immunological assay. Indeed, an indirect enzyme-linked immunosorbent assay (ELISA) with JCPyV VP1 mimotopes was used. JCPyV VP1 mimotopes consisted of synthetic peptides mimicking VP1 epitopes. Results Sera from CRC affected patients, evaluated using indirect ELISAs with synthetic mimotopes, showed a significant lower prevalence of IgG antibodies against JCPyV VP1 mimotopes (26%) compared to HS (51%), p<0.005. These data were confirmed by another method, the hemagglutination inhibition (HAI) assay. Altogether these results, i.e. the prevalence of serum IgG antibodies against JCPyV VP1 mimotopes from patients with CRC is approximately 50% lower than in HS, are of interest. Discussion Our data suggest that patients with CRC are significantly poor responders against JCPyV VP1 antigens. It is possible that CRC patients are affected by a specific immunological deregulation. This immunological dysfunction, revelled in CRC patients, may account for their predisposition to the colorectal carcinoma onset.
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Affiliation(s)
- Elena Torreggiani
- Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Ilaria Bononi
- Department of Translational Medicine, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Silvia Pietrobon
- Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Elisa Mazzoni
- Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Giovanni Guerra
- Clinical Laboratory Analysis, University-Hospital of Ferrara, Ferrara, Italy
| | - Carlo Feo
- Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Fernanda Martini
- Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Mauro Tognon
- Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
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Quercetin Inhibits Colorectal Cancer Cells Induced-Angiogenesis in Both Colorectal Cancer Cell and Endothelial Cell through Downregulation of VEGF-A/VEGFR2. Sci Pharm 2021. [DOI: 10.3390/scipharm89020023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer (CRC) aggressiveness is caused by cancer angiogenesis which promotes the cancer growth and metastasis associated with poor prognosis and poor survival. The vascular endothelial growth factor-A (VEGF-A) and its receptor (VEGFR-2) form the major signaling pathway in cancer angiogenesis. This study aimed to investigate the anti-angiogenesis activity of quercetin in both colorectal cancer cells and endothelial cells. The tube formation of human vein endothelial cells (HUVECs) was determined by using conditioned media of HT-29 cells treated with quercetin co-cultured with HUVECs. The VEGF-A and NF-κB p65 protein expressions in the quercetin-treated HT-29 cells were determined by fluorescence assay and Western blot analysis. The VEGFR-2 protein expression in HUVECs was determined after they were co-cultured with the quercetin-treated HT-29 cells. Quercetin markedly decreased the HT-29 cell-induced angiogenesis in HUVECs. NF-κB p65 and VEGF-A protein expression were also inhibited by quercetin. Moreover, quercetin significantly inhibited VEGFR-2 expression and translocation in HUVECs after they were co-cultured with high dose quercetin-treated HT-29 cells. Taken together, quercetin had an anti-angiogenesis effect on VEGF-A inhibition related to the NF-κB signaling pathway in the HT-29 cells and reduced VEGFR-2 expression and translocation in HUVECs.
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Assani I, Du Y, Wang CG, Chen L, Hou PL, Zhao SF, Feng Y, Liu LF, Sun B, Li Y, Liao ZX, Huang RZ. Anti-proliferative effects of diterpenoids from Sagittaria trifolia L. tubers on colon cancer cells by targeting the NF-κB pathway. Food Funct 2021; 11:7717-7726. [PMID: 32789317 DOI: 10.1039/d0fo00228c] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A new labdane-type diterpenoid, ent-19-ol-13-epi-manoyl oxide,19-undecane ester, together with ten known diterpenes, were isolated from the ethanolic crude extract of the fresh tubers of Sagittaria trifolia L. The chemical structures of these compounds were determined by extensive 2-D NMR experiments and by comparison with the data reported in the literature. These compounds showed different inhibitory effects on various human cancer cells. Among these, compound 11 exhibited potential inhibition effects against human colon cancer cells. Moreover, flow cytometry demonstrated that compound 11 arrested the cell cycle at the G1 phase and induced cellular apoptosis, accompanied by mitochondrial membrane potential reduction. Mechanistic studies revealed that treatment with compound 11 inhibited IKKα/β phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. Compound 11 also inhibited the expression of c-Myc, Cyclin D1, and Bcl-2, the downstream targets of NF-κB. Therefore, our findings provided insight into the anticancer components of Sagittaria trifolia L. tubers, which could facilitate their utilization as functional food ingredients.
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Affiliation(s)
- Israa Assani
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Ying Du
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Chun-Gu Wang
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Lei Chen
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Pei-Lei Hou
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Shi-Feng Zhao
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Yan Feng
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Ling-Fei Liu
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Bo Sun
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Yan Li
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Zhi-Xin Liao
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
| | - Ri-Zhen Huang
- College of Biotechnology, Guilin Medical University, Guilin 541100, China.
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Kumar S, Agnihotri N. Piperlongumine targets NF-κB and its downstream signaling pathways to suppress tumor growth and metastatic potential in experimental colon cancer. Mol Cell Biochem 2021; 476:1765-1781. [PMID: 33433833 DOI: 10.1007/s11010-020-04044-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 12/22/2020] [Indexed: 12/26/2022]
Abstract
NF-κB is the principle transcription factor and plays the central role in orchestrating chronic inflammation by regulating levels of cytokines, chemokines and growth factors. Piperlongumine (PL), a major alkaloid in the fruit of Piper longum Linn. has gained worldwide attention for its anticancer properties, however, its mechanism of action in the chemoprevention of colon cancer has not been investigated yet. Therefore, the present study was designed to elucidate the underlying molecular mechanism of PL in preventing DMH/DSS induced experimental colon cancer in mice. In the current study well established DMH/DSS induced experimental colon cancer mouse model was used to demonstrate the chemopreventive potential of PL. The expression of NF-κB and its downstream target proteins was evaluated mainly through western blotting. In addition, CAM assay, immunohistochemical staining and gelatin zymography was used to show anti-angiogenic and anti-invasive potential of PL. Additionally, important tumor biomarkers such as TSA, LASA, LDH and IL-6 levels were also estimated. The results of current study showed that PL was capable to inhibit NF-κB activation as well as its nuclear translocation. PL administration to DMH/DSS treated mice also inhibited the NF-κB downstream signaling cascades such as including COX-2 pathway, JAK/STAT pathway, β-catenin, Notch signaling pathway, angiogenesis and epithelial to mesenchymal transition pathway. The findings of the present study have claimed PL as promising chemopreventive agent for colon cancer with pleiotropic action. The current study emphasizes that regular consumption of PL can be an effective approach in the prevention of colon cancer in humans.
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Affiliation(s)
- Sandeep Kumar
- Department of Biochemistry, Basic Medical Science, Block-II, Sector-25, South Campus, Panjab University, Chandigarh, 160014, India
- Pharmacology and Toxicology Lab, Block J, CSIR-IHBT, Palampur, Himachal Pradesh, 176061, India
| | - Navneet Agnihotri
- Department of Biochemistry, Basic Medical Science, Block-II, Sector-25, South Campus, Panjab University, Chandigarh, 160014, India.
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NFκB-Activated COX2/PGE 2/EP4 Axis Controls the Magnitude and Selectivity of BCG-Induced Inflammation in Human Bladder Cancer Tissues. Cancers (Basel) 2021; 13:cancers13061323. [PMID: 33809455 PMCID: PMC7998891 DOI: 10.3390/cancers13061323] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/01/2021] [Accepted: 03/12/2021] [Indexed: 01/03/2023] Open
Abstract
Simple Summary The clinical effectiveness of Bacillus Calmette-Guérin (BCG) is limited to patients with early stages of bladder cancer (BlCa) and its effects are often transient. To understand the mechanisms limiting the effectiveness of BCG, we evaluated its impact on the human BlCa tumor microenvironment (TME) and the feasibility of its pharmacologic modulation. We observed that BCG non-selectively induces both CTL-attracting chemokines and Treg/MDSC attractants and suppressive factors in human BlCa tissue explants, in a mechanism involving NFκB-induced PGE2 synthesis and EP4 signaling. In contrast to non-selective impact of NFκB blockade on BCG-induced inflammation, the PGE2 antagonism selectively enhanced the BCG-driven production of CTL attractants but eliminated the induction of Treg/MDSC attractants and suppressive factors, enhancing the CTL migration but reducing Treg attraction to BCG-treated BlCa. Since intratumoral CTL accumulation predicts long term patient outcomes and the effectiveness of cancer immunotherapies, our data indicates the feasibility of targeting the PGE2-chemokine interplay to enhance the therapeutic effects of BCG. Abstract Bacillus Calmette-Guérin (BCG) is commonly used in the immunotherapy of bladder cancer (BlCa) but its effectiveness is limited to only a fraction of patients. To identify the factors that regulate the response of human BlCa tumor microenvironment (TME) to BCG, we used the ex vivo whole-tissue explant model. The levels of COX2 in the BCG-activated explants closely correlated with the local production of Treg- and MDSCS attractants and suppressive factors, while the baseline COX2 levels did not have predictive value. Accordingly, we observed that BCG induced high levels of MDSC- and Treg-attracting chemokines (CCL22, CXCL8, CXCL12) and suppressive factors (IDO1, IL-10, NOS2). These undesirable effects were associated with the nuclear translocation of phosphorylated NFκB, induction of COX2, the key enzyme controlling PGE2 synthesis, and elevation of a PGE2 receptor, EP4. While NFκB blockade suppressed both the desirable and undesirable components of BCG-driven inflammation, the inhibitors of PGE2 synthesis (Celecoxib or Indomethacin) or signaling (EP4-selective blocker, ARY-007), selectively eliminated the induction of MDSC/Treg attractants and immunosuppressive factors but enhanced the production of CTL attractants, CCL5, CXCL9 and CXCL10. PGE2 blockade allowed for the selectively enhanced migration of CTLs to the BCG-treated BlCa samples and eliminated the enhanced migration of Tregs. Since the balance between the CTLs and suppressive cells in the TME predicts the outcomes in patients with BlCa and other diseases, our data help to elucidate the mechanisms which limit the effectiveness of BCG therapies and identify new targets to enhance their therapeutic effects.
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Marzano F, Caratozzolo MF, Pesole G, Sbisà E, Tullo A. TRIM Proteins in Colorectal Cancer: TRIM8 as a Promising Therapeutic Target in Chemo Resistance. Biomedicines 2021; 9:biomedicines9030241. [PMID: 33673719 PMCID: PMC7997459 DOI: 10.3390/biomedicines9030241] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/16/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) represents one of the most widespread forms of cancer in the population and, as all malignant tumors, often develops resistance to chemotherapies with consequent tumor growth and spreading leading to the patient’s premature death. For this reason, a great challenge is to identify new therapeutic targets, able to restore the drugs sensitivity of cancer cells. In this review, we discuss the role of TRIpartite Motifs (TRIM) proteins in cancers and in CRC chemoresistance, focusing on the tumor-suppressor role of TRIM8 protein in the reactivation of the CRC cells sensitivity to drugs currently used in the clinical practice. Since the restoration of TRIM8 protein levels in CRC cells recovers chemotherapy response, it may represent a new promising therapeutic target in the treatment of CRC.
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Affiliation(s)
- Flaviana Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
| | - Mariano Francesco Caratozzolo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
| | - Graziano Pesole
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, “Aldo Moro”, 70125 Bari, Italy
| | - Elisabetta Sbisà
- Institute for Biomedical Technologies, National Research Council, CNR, 70126 Bari, Italy;
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, CNR, 70126 Bari, Italy; (F.M.); (M.F.C.); (G.P.)
- Correspondence:
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Bai H, Wang J, Phan CU, Chen Q, Hu X, Shao G, Zhou J, Lai L, Tang G. Cyclodextrin-based host-guest complexes loaded with regorafenib for colorectal cancer treatment. Nat Commun 2021; 12:759. [PMID: 33536421 PMCID: PMC7858623 DOI: 10.1038/s41467-021-21071-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG's anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.
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Affiliation(s)
- Hongzhen Bai
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Jianwei Wang
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Chi Uyen Phan
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Qi Chen
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Xiurong Hu
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Guoqiang Shao
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, 210029, Nanjing, PR China
| | - Jun Zhou
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China
| | - Lihua Lai
- Department of Pharmacology, School of Medicine, Zhejiang University, 310058, Hangzhou, PR China.
| | - Guping Tang
- Department of Chemistry, Zhejiang University, 310028, Hangzhou, PR China.
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Tang Y, Tang R, Tang M, Huang P, Liao Z, Zhou J, Zhou L, Su M, Chen P, Jiang J, Hu Y, Zhou Y, Liao Q, Zeng Z, Xiong W, Chen J, Nie S. LncRNA DNAJC3-AS1 Regulates Fatty Acid Synthase via the EGFR Pathway to Promote the Progression of Colorectal Cancer. Front Oncol 2021; 10:604534. [PMID: 33604287 PMCID: PMC7885865 DOI: 10.3389/fonc.2020.604534] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/14/2020] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. Recent studies have shown that long non-coding RNAs (lncRNAs) are involved in tumorigenesis and the development of CRC. By constructing a differential lncRNA expression profile, we screened gene chips and found that DNAJC3-AS1 was highly expressed in CRC tissues and was associated with poor prognosis in patients with CRC. Further, we proved through assays such as wound healing, colony formation, and Cell Counting Kit-8 (CCK8) that interfering with DNAJC3-AS1 could reduce the proliferation, migration, and invasion of CRC cells. Mechanically, we found that DNAJC3-AS1 regulates fatty acid synthase to promote the progression of CRC via the epidermal growth factor receptor/phosphatidylinositol 3-kinase/protein kinase B/nuclear factor κB signaling pathway. Therefore, DNAJC3-AS1 may be a new target for the diagnosis and therapy of CRC.
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Affiliation(s)
- Yanyan Tang
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Central Laboratory, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, China
| | - Rui Tang
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Ultrasound, Department of Stomatology, Third Xiangya Hospital, Central South University, Changsha, China.,The University of South China, Hengyang, China
| | - Mengtian Tang
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,The University of South China, Hengyang, China
| | - Ping Huang
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhiqiang Liao
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Jumei Zhou
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Lianqing Zhou
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Min Su
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Central Laboratory, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, China
| | - Pan Chen
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Central Laboratory, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, China
| | - Jiarui Jiang
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yingbin Hu
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yujuan Zhou
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - QianJin Liao
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Central Laboratory, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, China
| | - Zhaoyang Zeng
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Wei Xiong
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Junhong Chen
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,The University of South China, Hengyang, China
| | - Shaolin Nie
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Department of Colorectal Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
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Chung SY, Chao TC, Su Y. The Stemness-High Human Colorectal Cancer Cells Promote Angiogenesis by Producing Higher Amounts of Angiogenic Cytokines via Activation of the Egfr/Akt/Nf-κB Pathway. Int J Mol Sci 2021; 22:ijms22031355. [PMID: 33573006 PMCID: PMC7866396 DOI: 10.3390/ijms22031355] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/22/2021] [Accepted: 01/27/2021] [Indexed: 12/27/2022] Open
Abstract
Purpose: Cancer stem cells (CSCs) are responsible for cancer metastasis by stimulating tumor angiogenesis via various mechanisms. To elucidate the potential of the stemness-high human colorectal cancer (CRC) cells (i.e., CRCSCs) in activating angiogenesis, effects of the GATA6-overexpressing HCT-116 and HT-29 human CRC clones established previously by us in promoting the angiogenesis of human umbilical vein endothelial cells (HUVECs) were examined. Methods: Angiogenesis-promoting effects (i.e., migration, invasion, DNA synthesis, and tube formation) in HUVECs of the conditioned media (CM) from various human CRC clones were analyzed. MMP activities were assessed using a zymography assay. Western blotting and selective inhibitors were used to dissect the signaling pathway involved. IHC was used to examine the vascular density in tumor xenografts. Results: We found that the conditioned media (CM) collected from the GATA6-overexpressing clones enhanced angiogenesis of HUVECs more effectively which might be attributed partly to a higher MMP-9 production by HUVECs. Subsequently, elevated levels of IL-8 and VEGF-A were detected in the CM whose tube formation-enhancing activities were abolished by the co-treatment with either a VEGFR2 inhibitor or an IL-8 neutralizing antibody. Interestingly, increased production of these cytokines in the GATA6-overexpressing clones was due to an EGFR/AKT-mediated activation of NF-κB. Furthermore, not only were the levels of CD31 and endomucin but also the blood vessel density was much higher in the xenograft tumors grown from these clones. Conclusion: Our findings demonstrate that human CRCSCs promote a stronger angiogenesis by producing higher amounts of angiogenic factors through activation of the EGFR/AKT/NF-κB pathway.
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Affiliation(s)
- Shin-Yi Chung
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Shi-Pai, Taipei 11221, Taiwan;
| | - Ta-Chung Chao
- Department of Oncology, Division of Medical Oncology, Taipei Veterans General Hospital, Taipei 11221, Taiwan;
- Faculty of Medicine, School of Medicine, National Yang-Min University, Taipei 11221, Taiwan
| | - Yeu Su
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Shi-Pai, Taipei 11221, Taiwan;
- Correspondence: ; Fax: +886-2-2825-0883
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Liaño-Pons J, Lafita-Navarro MC, García-Gaipo L, Colomer C, Rodríguez J, von Kriegsheim A, Hurlin PJ, Ourique F, Delgado MD, Bigas A, Espinosa L, León J. A novel role of MNT as a negative regulator of REL and the NF-κB pathway. Oncogenesis 2021; 10:5. [PMID: 33419981 PMCID: PMC7794610 DOI: 10.1038/s41389-020-00298-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 11/20/2020] [Accepted: 12/02/2020] [Indexed: 01/29/2023] Open
Abstract
MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix-loop-helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT-REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT-REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.
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Affiliation(s)
- Judit Liaño-Pons
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, Stockholm, Sweden
| | - M Carmen Lafita-Navarro
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
- Department of Cell Biology UT Southwestern Medical Center, Dallas, TX, USA
| | - Lorena García-Gaipo
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
| | - Carlota Colomer
- Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain
| | - Javier Rodríguez
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Alex von Kriegsheim
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
- Edinburgh Cancer Research Center, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Peter J Hurlin
- Shriners Hospitals for Children Research Center, Department of Cell, Developmental and Cancer Biology and Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, Portland, OR, USA
| | - Fabiana Ourique
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
- Dept. of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
| | - M Dolores Delgado
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
| | - Anna Bigas
- Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain
| | - Lluis Espinosa
- Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain
| | - Javier León
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain.
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50
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Choo J, Heo G, Pothoulakis C, Im E. Posttranslational modifications as therapeutic targets for intestinal disorders. Pharmacol Res 2021; 165:105412. [PMID: 33412276 DOI: 10.1016/j.phrs.2020.105412] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/14/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023]
Abstract
A variety of biological processes are regulated by posttranslational modifications. Posttranslational modifications including phosphorylation, ubiquitination, glycosylation, and proteolytic cleavage, control diverse physiological functions in the gastrointestinal tract. Therefore, a better understanding of their implications in intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer would provide a basis for the identification of novel biomarkers as well as attractive therapeutic targets. Posttranslational modifications can be common denominators, as well as distinct biomarkers, characterizing pathological differences of various intestinal diseases. This review provides experimental evidence that identifies changes in posttranslational modifications from patient samples, primary cells, or cell lines in intestinal disorders, and a summary of carefully selected information on the use of pharmacological modulators of protein modifications as therapeutic options.
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Affiliation(s)
- Jieun Choo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Gwangbeom Heo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Charalabos Pothoulakis
- Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
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