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Golovina E, Eaton C, Cox V, Andel J, Savvulidi Vargova K. Mechanism of Action of circRNA/miRNA Network in DLBCL. Noncoding RNA 2025; 11:22. [PMID: 40126346 PMCID: PMC11932212 DOI: 10.3390/ncrna11020022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 02/06/2025] [Accepted: 02/27/2025] [Indexed: 03/25/2025] Open
Abstract
Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.
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Affiliation(s)
- Elena Golovina
- First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 12108 Prague, Czech Republic; (E.G.); (C.E.)
| | - Cory Eaton
- First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 12108 Prague, Czech Republic; (E.G.); (C.E.)
| | - Virginia Cox
- First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 12108 Prague, Czech Republic; (E.G.); (C.E.)
| | - Jozef Andel
- First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 12108 Prague, Czech Republic; (E.G.); (C.E.)
- Faculty of Science, Molecular Biology and Genetics of Eukaryotes, Charles University, 12800 Prague, Czech Republic
| | - Karina Savvulidi Vargova
- First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 12108 Prague, Czech Republic; (E.G.); (C.E.)
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Vasudevan MT, Rangaraj K, Ramesh R, Muthusami S, Govindasamy C, Khan MI, Arulselvan P, Muruganantham B. Inhibitory effects of Gracilaria edulis and Gracilaria salicornia against the MGMT and VEGFA biomarkers involved in the onset and advancement of glioblastoma using in silico and in vitro approaches. Biotechnol Appl Biochem 2025; 72:207-224. [PMID: 39168850 DOI: 10.1002/bab.2657] [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: 06/04/2024] [Accepted: 08/05/2024] [Indexed: 08/23/2024]
Abstract
Glioblastoma (GBM), an aggressive primary brain tumor originating from glial cells, poses significant treatment challenges due to its rapid growth and invasiveness. The exact mechanisms of GBM's brain damage remain unclear. This study examines primary molecular markers commonly assessed in GBM patients, including brain-derived neurotrophic factor (BDNF), platelet-derived growth factor receptor A (PDGFRA), O6-methylguanine DNA methyltransferase (MGMT), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor A (VEGFA) using computational approaches. The study revealed significant differences (p ≤ 0.05) in PDGFRA, EGFR, and VEGFA expression rates, which are particularly interesting. Additionally, MGMT and VEGFA showed higher hazard ratios. Expression levels of MGMT and VEGFA were visualized in immune and malignant cells using single-cell RNA datasets GSE103224 and GSE148842. From a total of 48 compounds in Gracilaria edulis and 86 in Gracilaria salicornia, we identified 15 compounds capable of crossing the blood-brain barrier. Notably, 2-tridecanone (binding affinity [BA] = -4.2 kcal/mol; root mean square deviation [RMSD] = 1.479 Å) and decanoic acid, ethyl ester (BA = -4.2 kcal/mol; RMSD = 1.702 Å) from G. edulis interacted with MGMT via hydrogen bonds. The compound alpha-terpineol interacted with MGMT (BA = -5.7 kcal/mol; RMSD = 0.501 Å) and VEGFA (BA = -4.7 kcal/mol; RMSD = 2.483 Å). Ethanolic and methanolic extracts from G. edulis and G. salicornia demonstrated mild anti-cell proliferation properties in the GBM LN-229 cell line, suggesting potential therapeutic benefits. This study highlights the significance of molecular markers and natural compounds in understanding and potentially treating GBM.
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Affiliation(s)
- Miji Thandaserry Vasudevan
- Department of Biochemistry, Centre for Bioinformatics, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India
| | - Kaviyaprabha Rangaraj
- Department of Biochemistry, Centre for Bioinformatics, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India
| | - Ragupathi Ramesh
- Department of Biotechnology, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India
| | - Sridhar Muthusami
- Department of Biochemistry, Centre for Cancer Research, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India
| | - Chandramohan Govindasamy
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Muhammad Ibrar Khan
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Palanisamy Arulselvan
- Department of Chemistry, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu, India
| | - Bharathi Muruganantham
- Department of Biochemistry, Centre for Bioinformatics, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India
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de Korte D, Hoekstra M. Protein Arginine Methyltransferase 1: A Multi-Purpose Player in the Development of Cancer and Metabolic Disease. Biomolecules 2025; 15:185. [PMID: 40001488 PMCID: PMC11852820 DOI: 10.3390/biom15020185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Protein arginine methyltransferase 1 (PRMT1) is the main PRMT family member involved in the formation of monomethylarginine and asymmetric dimethylarginine on its protein substrates. Many protein substrates of PRMT1 are key mediators of cell proliferation and oncogenesis. As such, the function of PRMT1 has been most prominently investigated in the context of cancer development. However, recent in vitro and in vivo studies have highlighted that PRMT1 may also promote metabolic disorders. With the current review, we aim to present an in-depth overview of how PRMT1 influences epigenetic modulation, transcriptional regulation, DNA damage repair, and signal transduction in cancer. Furthermore, we summarize the current knowledge regarding the role of PRMT1 in metabolic reprogramming, lipid metabolism, and glucose metabolism and describe the association of PRMT1 with numerous metabolic pathologies such as obesity, liver disease, and type 2 diabetes. It has become apparent that inhibiting the function of PRMT1 will likely serve as the most beneficial therapeutic approach, since several PRMT1 inhibitors have already been shown to exert positive effects on both cancer and metabolic disease in preclinical settings. However, pharmacological PRMT1 inhibition has not yet been shown to be therapeutically effective in clinical studies.
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Affiliation(s)
| | - Menno Hoekstra
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands;
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Shi JH, Shi YB, Qiu ST, Song Y. Role of the Transcription Factor FoxO in Type 2 Diabetes and Its Complications. Crit Rev Eukaryot Gene Expr 2025; 35:85-103. [PMID: 39964972 DOI: 10.1615/critreveukaryotgeneexpr.2025057309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
FoxO proteins represent a subfamily of the forkhead box family (Fox) superfamily of proteins. It is involved in cell proliferation, differentiation, oxidative stress, apoptosis as well as tumors and metabolic disorders by regulating cellular functions. This paper aims to summarize the role of the transcription factor FoxO in type 2 diabetes and its complications, which may add to the potential of FoxO as a therapeutic target for future research. The transcription factor FoxO is expressed in various tissues and participates in various bodily functions including cell proliferation, differentiation, apoptosis, tumor therapy, and metabolic processes, playing a crucial role in the human body. FoxO plays a positive role in attenuating oxidative stress, inflammation, and metabolic disorders, which are the main causes of type 2 diabetes and its complications. FoxO plays an important role in the regulation of type 2 diabetes and its complications, and more precise targeting studies of FoxO will help to prevent, regulate, and treat diabetes-related diseases.
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Affiliation(s)
- Jing Hui Shi
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Yi Biao Shi
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Si Tian Qiu
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Ying Song
- Department of Pharmacology, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou City, Zhejiang Province 310014, P.R. China
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Hill M, Stapleton S, Nguyen PT, Sais D, Deutsch F, Gay VC, Marsh DJ, Tran N. The potential regulation of the miR-17-92a cluster by miR-21. Int J Biochem Cell Biol 2025; 178:106705. [PMID: 39615668 DOI: 10.1016/j.biocel.2024.106705] [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: 05/30/2024] [Revised: 10/31/2024] [Accepted: 11/26/2024] [Indexed: 12/16/2024]
Abstract
MicroRNAs (miRNA,miRs) are small noncoding RNAs that are ubiquitously expressed in all mammalian cells. Their primary function is the regulation of nascent RNA transcripts by direct binding to regions on the target. There is now exciting data to suggest that these miRNAs can bind to other miRNAs, and this may have a broader impact on gene regulation in disease states. The oncomiR miR-21 is one of the highest-expressing miRNAs in cancer cells, and in this study, we characterise which miRNAs could be potential targets of miR-21. In cancer cells delivered with a miR-21 mimic, there was an observable shift of the miRNA milieu. We demonstrate that the miR-17-92a cluster, which harbours six miRNA members, may be a target for miR-21 regulation. Additionally, the primary transcript of miR-17-92a was reduced in the presence of miR-21. In the broader context of miR:miR regulation, overexpression of miR-21 shifted the expression of more than 150 miRNAs, including those known to regulate genes in cancer pathways such as the MAPK signalling and FoxO pathways. This study expands upon our limited understanding of miR:miR regulatory network and reinforces the concept that miRNAs can regulate each other, thereby influencing broader gene networks.
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Affiliation(s)
- Meredith Hill
- School of Biomedical Engineering, Faculty of Engineering, and Information Technology, University of Technology Sydney, Australia
| | - Sarah Stapleton
- School of Biomedical Engineering, Faculty of Engineering, and Information Technology, University of Technology Sydney, Australia
| | | | - Dayna Sais
- School of Biomedical Engineering, Faculty of Engineering, and Information Technology, University of Technology Sydney, Australia
| | - Fiona Deutsch
- School of Biomedical Engineering, Faculty of Engineering, and Information Technology, University of Technology Sydney, Australia
| | - Valerie C Gay
- School of Electrical and Data Engineering, Faculty of Engineering, and Information Technology, University of Technology Sydney, Australia
| | - Deborah J Marsh
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Australia
| | - Nham Tran
- School of Biomedical Engineering, Faculty of Engineering, and Information Technology, University of Technology Sydney, Australia.
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Zhong H, Zhou Z, Wang H, Wang R, Shen K, Huang R, Wang Z. The Biological Roles and Clinical Applications of the PI3K/AKT Pathway in Targeted Therapy Resistance in HER2-Positive Breast Cancer: A Comprehensive Review. Int J Mol Sci 2024; 25:13376. [PMID: 39769140 PMCID: PMC11677710 DOI: 10.3390/ijms252413376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is a highly invasive and malignant type of tumor. Due to its resistance to HER2-targeted therapy, HER2+ BC has a poor prognosis and a tendency for metastasis. Understanding the mechanisms underlying this resistance and developing effective treatments for HER2+ BC are major research challenges. The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, which is frequently altered in cancers, plays a critical role in cellular proliferation and drug resistance. This signaling pathway activates various downstream pathways and exhibits complex interactions with other signaling networks. Given the significance of the PI3K/AKT pathway in HER2+ BC, several targeted drugs are currently in development. Multiple drugs have entered clinical trials or gained market approval, bringing new hope for HER2+ BC therapy. However, new drugs and therapies raise concerns related to safety, regulation, and ethics. Populations of different races and disease statuses exhibit varying responses to treatments. Therefore, in this review, we summarize current knowledge on the alteration and biological roles of the PI3K/AKT pathway, as well as its clinical applications and perspectives, providing new insights for advancing targeted therapies in HER2+ BC.
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Affiliation(s)
| | | | | | | | | | - Renhong Huang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (H.Z.); (Z.Z.); (H.W.); (R.W.); (K.S.)
| | - Zheng Wang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (H.Z.); (Z.Z.); (H.W.); (R.W.); (K.S.)
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7
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Mallick S, Duttaroy AK, Dutta S. The PIK3CA gene and its pivotal role in tumor tropism of triple-negative breast cancer. Transl Oncol 2024; 50:102140. [PMID: 39369580 PMCID: PMC11491976 DOI: 10.1016/j.tranon.2024.102140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 09/04/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024] Open
Abstract
The PIK3CA gene is a linchpin in the intricate molecular network governing triple-negative breast cancer (TNBC) tumor tropism, serving as a focal point for understanding this aggressive disease. Anchored within the PI3K/AKT/mTOR signaling axis, PIK3CA mutations exert substantial influence, driving cellular processes that highlight the unique biology of TNBC. This review meticulously highlights the association between PIK3CA mutations and distinct TNBC subtypes, elucidating the gene's multifaceted contributions to tumor tropism. Molecular dissection reveals how PIK3CA mutations dynamically modulate chemokine responses, growth factor signaling, and extracellular matrix interactions, orchestrating the complex migratory behaviour characteristic of TNBC cells. A detailed exploration of PIK3CA-targeted strategies in the therapeutic arena is presented, outlining the current landscape of clinical trials and precision medicine approaches. As the scientific narrative converges, this review underscores the critical role of PIK3CA in shaping the molecular intricacies of TNBC tumor tropism and illuminates pathways toward tailored interventions, promising a paradigm shift in the clinical management of TNBC.
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Affiliation(s)
- Sumit Mallick
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Mangalore, Karnataka, India
| | - Asim K Duttaroy
- Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Norway.
| | - Suman Dutta
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK; Dorothy Crowfoot Hodgkin Building, Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
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Ferguson KM, Blin C, Garcia-Diaz C, Bulstrode H, Bardini Bressan R, McCarten K, Pollard SM. Modelling quiescence exit of neural stem cells reveals a FOXG1-FOXO6 axis. Dis Model Mech 2024; 17:dmm052005. [PMID: 39499086 PMCID: PMC11625887 DOI: 10.1242/dmm.052005] [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: 06/25/2024] [Accepted: 10/30/2024] [Indexed: 11/07/2024] Open
Abstract
The molecular mechanisms controlling the balance of quiescence and proliferation in adult neural stem cells (NSCs) are often deregulated in brain cancers such as glioblastoma multiforme (GBM). Previously, we reported that FOXG1, a forebrain-restricted neurodevelopmental transcription factor, is frequently upregulated in glioblastoma stem cells (GSCs) and limits the effects of cytostatic pathways, in part by repression of the tumour suppressor Foxo3. Here, we show that increased FOXG1 upregulates Foxo6, a more recently discovered FOXO family member with potential oncogenic functions. Although genetic ablation of Foxo6 in proliferating NSCs had no effect on the cell cycle or entry into quiescence, we found that Foxo6-null NSCs could no longer efficiently exit quiescence following FOXG1 elevation. Increased Foxo6 resulted in the formation of large acidic vacuoles, reminiscent of Pak1-regulated macropinocytosis. Consistently, Pak1 expression was upregulated by FOXG1 overexpression and downregulated upon FOXO6 loss in proliferative NSCs. These data suggest a pro-oncogenic role for FOXO6, downstream of GBM-associated elevated FOXG1, in controlling quiescence exit, and shed light on the potential functions of this underexplored FOXO family member.
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Affiliation(s)
- Kirsty M. Ferguson
- Centre for Regenerative Medicine, Institute for Regeneration and Repair and Edinburgh Cancer Research UK Centre, The University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Carla Blin
- Centre for Regenerative Medicine, Institute for Regeneration and Repair and Edinburgh Cancer Research UK Centre, The University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Claudia Garcia-Diaz
- Centre for Regenerative Medicine, Institute for Regeneration and Repair and Edinburgh Cancer Research UK Centre, The University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Harry Bulstrode
- Centre for Regenerative Medicine, Institute for Regeneration and Repair and Edinburgh Cancer Research UK Centre, The University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Raul Bardini Bressan
- Centre for Regenerative Medicine, Institute for Regeneration and Repair and Edinburgh Cancer Research UK Centre, The University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Katrina McCarten
- Centre for Regenerative Medicine, Institute for Regeneration and Repair and Edinburgh Cancer Research UK Centre, The University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Steven M. Pollard
- Centre for Regenerative Medicine, Institute for Regeneration and Repair and Edinburgh Cancer Research UK Centre, The University of Edinburgh, Edinburgh EH16 4UU, UK
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Li X, Liu B, Huang D, Ma N, Xia J, Zhao X, Duan Y, Li F, Lin S, Tang S, Li Q, Rao J, Zhang X. Chidamide triggers pyroptosis in T-cell lymphoblastic lymphoma/leukemia via the FOXO1/GSDME axis. Chin Med J (Engl) 2024:00029330-990000000-01266. [PMID: 39445538 DOI: 10.1097/cm9.0000000000003214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS Our study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
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Affiliation(s)
- Xinlei Li
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Bangdong Liu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Dezhi Huang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Naya Ma
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Jing Xia
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Xianlan Zhao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Yishuo Duan
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Fu Li
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Shijia Lin
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Shuhan Tang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Qiong Li
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Jun Rao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Jinfeng Laboratory, Chongqing 400037, China
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Suzauddula M, Kobayashi K, Park S, Sun XS, Wang W. Bioengineered Anthocyanin-Enriched Tomatoes: A Novel Approach to Colorectal Cancer Prevention. Foods 2024; 13:2991. [PMID: 39335919 PMCID: PMC11430996 DOI: 10.3390/foods13182991] [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: 08/10/2024] [Revised: 09/11/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health challenge, with barriers to effective prevention and treatment including tumor recurrence, chemoresistance, and limited overall survival rates. Anthocyanins, known for their strong anti-cancer properties, have shown promise in preventing and suppressing various cancers, including CRC. However, natural sources of anthocyanins often fail to provide sufficient quantities needed for therapeutic effects. Bioengineered crops, particularly anthocyanin-enriched tomatoes, offer a viable solution to enhance anthocyanin content. Given its large-scale production and consumption, tomatoes present an ideal target for bioengineering efforts aimed at increasing dietary anthocyanin intake. This review provides an overview of anthocyanins and their health benefits, elucidating the mechanisms by which anthocyanins modulate the transcription factors involved in CRC development. It also examines case studies demonstrating the successful bioengineering of tomatoes to boost anthocyanin levels. Furthermore, the review discusses the effects of anthocyanin extracts from bioengineered tomatoes on CRC prevention, highlighting their role in altering metabolic pathways and reducing tumor-related inflammation. Finally, this review addresses the challenges associated with bioengineering tomatoes and proposes future research directions to optimize anthocyanin enrichment in tomatoes.
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Affiliation(s)
- Md Suzauddula
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
| | - Kaori Kobayashi
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
| | - Sunghun Park
- Department of Horticulture and Nature Resources, Kansas State University, Manhattan, KS 66506, USA;
| | - Xiuzhi Susan Sun
- Department of Grain Science and Industry, Kansas State University, Manhattan, KS 66506, USA;
| | - Weiqun Wang
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
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11
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Lin Z, Li Y, Zhao J, Li J, Pan S, Wang X, Lin H, Lin Z. Exploring the environmental contamination toxicity and potential carcinogenic pathways of perfluorinated and polyfluoroalkyl substances (PFAS): An integrated network toxicology and molecular docking strategy. Heliyon 2024; 10:e37003. [PMID: 39286118 PMCID: PMC11402918 DOI: 10.1016/j.heliyon.2024.e37003] [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: 08/09/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
The objective of this study was to investigate the potential carcinogenic toxicity and mechanisms of PFAS in thyroid, renal, and testicular cancers base on network toxicology and molecular docking techniques. Structural modeling was performed to predict relevant toxicity information, and compounds and cancer-related targets were screened in multiple databases. The interaction of PFAS with three cancers and their key protein targets were explored by combining protein network analysis, enrichment analysis and molecular docking techniques. PFOA, PFOS, and PFHXS exhibited significant carcinogenic and cytotoxic effects. These compounds may induce cancer by mediating active oxygen metabolism and the transduction of phosphatidylinositol 3-kinase/protein kinase B signaling pathway through genes such as ALB, mTOR, MDM2, and ERBB2. Furthermore, the underlying toxic mechanisms may be linked to the pathways in cancer, chemical carcinogenesis through reactive oxygen species/receptor activation, and the FoxO signaling pathway. The results contribute to a comprehensive understanding of the effects of these environmental pollutants on genes, proteins, and metabolic pathways in living organisms. It revealed their toxicity mechanisms in inducing thyroid, renal, and testicular cancers, and provided a solid theoretical foundation for designing new environmental control strategies and drug screening initiatives. Additionally, the integrated application of network toxicology and molecular docking technology can enhance our understanding of the toxicity and mechanisms of unknown environmental pollutants, which is beneficial for protecting the environment and human health.
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Affiliation(s)
- Zhi Lin
- College of Pharmacy, Changchun University of Chinese Medicine, China
| | - Yvmo Li
- College of Pharmacy, Changchun University of Chinese Medicine, China
| | - Jiarui Zhao
- College of Pharmacy, Changchun University of Chinese Medicine, China
| | - Jun Li
- College of Pharmacy, Changchun University of Chinese Medicine, China
| | - Shuang Pan
- College of Pharmacy, Changchun University of Chinese Medicine, China
| | - Xinhe Wang
- College of Pharmacy, Changchun University of Chinese Medicine, China
| | - He Lin
- College of Pharmacy, Changchun University of Chinese Medicine, China
| | - Zhe Lin
- College of Pharmacy, Changchun University of Chinese Medicine, China
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12
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Santini L, Kowald S, Cerron-Alvan LM, Huth M, Fabing AP, Sestini G, Rivron N, Leeb M. FoxO transcription factors actuate the formative pluripotency specific gene expression programme. Nat Commun 2024; 15:7879. [PMID: 39251582 PMCID: PMC11384738 DOI: 10.1038/s41467-024-51794-9] [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: 01/24/2024] [Accepted: 08/16/2024] [Indexed: 09/11/2024] Open
Abstract
Naïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, embryonic stem cells (ESCs) transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localisation of FoxO TFs in naïve ESCs. PTEN-mediated reduction of AKT activity upon exit from naïve pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for the activation of the formative pluripotency-specific GRN. Our work uncovers a pivotal role for FoxO TFs in establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.
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Affiliation(s)
- Laura Santini
- Max Perutz Laboratories Vienna, University of Vienna, Vienna BioCenter, 1030, Vienna, Austria
- Vienna BioCenter PhD Program, Doctoral School of the University of Vienna, Medical University of Vienna, 1030, Vienna, Austria
| | - Saskia Kowald
- Max Perutz Laboratories Vienna, University of Vienna, Vienna BioCenter, 1030, Vienna, Austria
| | - Luis Miguel Cerron-Alvan
- Max Perutz Laboratories Vienna, University of Vienna, Vienna BioCenter, 1030, Vienna, Austria
- Vienna BioCenter PhD Program, Doctoral School of the University of Vienna, Medical University of Vienna, 1030, Vienna, Austria
| | - Michelle Huth
- Max Perutz Laboratories Vienna, University of Vienna, Vienna BioCenter, 1030, Vienna, Austria
- Vienna BioCenter PhD Program, Doctoral School of the University of Vienna, Medical University of Vienna, 1030, Vienna, Austria
| | - Anna Philina Fabing
- Max Perutz Laboratories Vienna, University of Vienna, Vienna BioCenter, 1030, Vienna, Austria
| | - Giovanni Sestini
- Vienna BioCenter PhD Program, Doctoral School of the University of Vienna, Medical University of Vienna, 1030, Vienna, Austria
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, 1030, Vienna, Austria
| | - Nicolas Rivron
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, 1030, Vienna, Austria
| | - Martin Leeb
- Max Perutz Laboratories Vienna, University of Vienna, Vienna BioCenter, 1030, Vienna, Austria.
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13
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Galant LS, Doblado L, Radi R, de Bem AF, Monsalve M. Culture of Bovine Aortic Endothelial Cells in Galactose Media Enhances Mitochondrial Plasticity and Changes Redox Sensing, Altering Nrf2 and FOXO3 Levels. Antioxidants (Basel) 2024; 13:873. [PMID: 39061940 PMCID: PMC11274175 DOI: 10.3390/antiox13070873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/06/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Understanding the complex biological processes of cells in culture, particularly those related to metabolism, can be biased by culture conditions, since the choice of energy substrate impacts all of the main metabolic pathways. When glucose is replaced by galactose, cells decrease their glycolytic flux, working as an in vitro model of limited nutrient availability. However, the effect of these changes on related physiological processes such as redox control is not well documented, particularly in endothelial cells, where mitochondrial oxidation is considered to be low. We evaluated the differences in mitochondrial dynamics and function in endothelial cells exposed to galactose or glucose culture medium. We observed that cells maintained in galactose-containing medium show a higher mitochondrial oxidative capacity, a more fused mitochondrial network, and higher intercellular coupling. These factors are documented to impact the cellular response to oxidative stress. Therefore, we analyzed the levels of two main redox regulators and found that bovine aortic endothelial cells (BAEC) in galactose media had higher levels of FOXO3 and lower levels of Nrf2 than those in glucose-containing media. Thus, cultures of endothelial cells in a galactose-containing medium may provide a more suitable target for the study of in vitro mitochondrial-related processes than those in glucose-containing media; the medium deeply influences redox signaling in these cells.
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Affiliation(s)
- Leticia Selinger Galant
- Department of Biochemistry, Federal University of Santa Catarina, Florianópolis 88040900, Brazil;
- Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain;
| | - Laura Doblado
- Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain;
| | - Rafael Radi
- Departamento de Bioquimica y Centro de Investigaciones Biomedicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 2125, Uruguay;
| | - Andreza Fabro de Bem
- Department of Biochemistry, Federal University of Santa Catarina, Florianópolis 88040900, Brazil;
- Department of Physiological Science, Institute for Biological Sciences, University of Brasília, Brasília 70910900, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Rio de Janeiro 21040360, Brazil
| | - Maria Monsalve
- Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain;
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14
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Šetinc M, Celinšćak Ž, Bočkor L, Zajc Petranović M, Stojanović Marković A, Peričić Salihović M, Deelen J, Škarić-Jurić T. The role of longevity-related genetic variant interactions as predictors of survival after 85 years of age. Mech Ageing Dev 2024; 219:111926. [PMID: 38484896 PMCID: PMC11166054 DOI: 10.1016/j.mad.2024.111926] [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: 01/26/2024] [Revised: 02/27/2024] [Accepted: 03/11/2024] [Indexed: 03/26/2024]
Abstract
Genome-wide association studies and candidate gene studies have identified several genetic variants that might play a role in achieving longevity. This study investigates interactions between pairs of those single nucleotide polymorphisms (SNPs) and their effect on survival above the age of 85 in a sample of 327 Croatian individuals. Although none of the SNPs individually showed a significant effect on survival in this sample, 14 of the 359 interactions tested (between SNPs not in LD) reached the level of nominal significance (p<0.05), showing a potential effect on late-life survival. Notably, SH2B3 rs3184504 interacted with different SNPs near TERC, TP53 rs1042522 with different SNPs located near the CDKN2B gene, and CDKN2B rs1333049 with different SNPs in FOXO3, as well as with LINC02227 rs2149954. The other interaction pairs with a possible effect on survival were FOXO3 rs2802292 and ERCC2 rs50871, IL6 rs1800795 and GHRHR rs2267723, LINC02227 rs2149954 and PARK7 rs225119, as well as PARK7 rs225119 and PTPN1 rs6067484. These interactions remained significant when tested together with a set of health-related variables that also had a significant effect on survival above 85 years. In conclusion, our results confirm the central role of genetic regulation of insulin signalling and cell cycle control in longevity.
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Affiliation(s)
- Maja Šetinc
- Institute for Anthropological Research, Zagreb 10000, Croatia; Centre for Applied Bioanthropology, Institute for Anthropological Research, Zagreb 10000, Croatia.
| | | | - Luka Bočkor
- Institute for Anthropological Research, Zagreb 10000, Croatia; Centre for Applied Bioanthropology, Institute for Anthropological Research, Zagreb 10000, Croatia
| | | | | | | | - Joris Deelen
- Max Planck Institute for Biology of Ageing, Cologne 50931, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
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15
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Haider S, Chakraborty S, Chowdhury G, Chakrabarty A. Opposing Interplay between Nuclear Factor Erythroid 2-Related Factor 2 and Forkhead BoxO 1/3 is Responsible for Sepantronium Bromide's Poor Efficacy and Resistance in Cancer cells: Opportunity for Combination Therapy in Triple Negative Breast Cancer. ACS Pharmacol Transl Sci 2024; 7:1237-1251. [PMID: 38751638 PMCID: PMC11091984 DOI: 10.1021/acsptsci.3c00279] [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: 10/11/2023] [Revised: 03/29/2024] [Accepted: 04/10/2024] [Indexed: 05/18/2024]
Abstract
Survivin, a cancer-cell-specific multifunctional protein, is regulated by many oncogenic signaling pathways and an effective therapeutic target. Although, several types of survivin-targeting agents have been developed over the past few decades, none of them received clinical approval. This could be because survivin expression is tightly controlled by the feedback interaction between different signaling molecules. Of the several signaling pathways that are known to regulate survivin expression, the phosphatidylinositol 3-kinase/AKT serine-threonine kinase/forkhead boxO (PI3K/AKT/FoxO) pathway is well-known for feedback loops constructed by cross-talk among different molecules. Using sepantronium bromide (YM155), the first of its class of survivin-suppressant, we uncovered the existence of an interesting cross-talk between Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) and FoxO transcription factors that also contributes to YM155 resistance in triple negative breast cancer (TNBC) cells. Pharmacological manipulation to interrupt this interaction not only helped restore/enhance the drug-sensitivity but also prompted effective immune clearance of cancer cells. Because the YM155-induced reactive oxygen species (ROS) initiates this feedback, we believe that it will be occurring for many ROS-producing chemotherapeutic agents. Our work provides a rational explanation for the poor efficacy of YM155 compared to standard chemotherapy in clinical trials. Finally, the triple drug combination approach used herein might help reintroducing YM155 into the clinical pipeline, and given the high survivin expression in TNBC cells in general, it could be effective in treating this subtype of breast cancer.
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Affiliation(s)
- Shaista Haider
- Department
of Life Sciences, Shiv Nadar Institution
of Eminence, Greater Noida Gautam
Buddha Nagar Uttar Pradesh 201314, India
| | - Shayantani Chakraborty
- Department
of Life Sciences, Shiv Nadar Institution
of Eminence, Greater Noida Gautam
Buddha Nagar Uttar Pradesh 201314, India
| | - Goutam Chowdhury
- Independent
Researcher, Greater Noida Gautam Buddha Nagar Uttar Pradesh 201308, India
| | - Anindita Chakrabarty
- Department
of Life Sciences, Shiv Nadar Institution
of Eminence, Greater Noida Gautam
Buddha Nagar Uttar Pradesh 201314, India
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16
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Xiong X, Yang C, Jin Y, Zhang R, Wang S, Gan L, Hou S, Bao Y, Zeng Z, Ye Y, Gao Z. ABHD6 suppresses colorectal cancer progression via AKT signaling pathway. Mol Carcinog 2024; 63:647-662. [PMID: 38197491 DOI: 10.1002/mc.23678] [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: 07/19/2023] [Revised: 12/05/2023] [Accepted: 12/28/2023] [Indexed: 01/11/2024]
Abstract
Colorectal cancer (CRC) continues to be a prevalent malignancy, posing a significant risk to human health. The involvement of alpha/beta hydrolase domain 6 (ABHD6), a serine hydrolase family member, in CRC development was suggested by our analysis of clinical data. However, the role of ABHD6 in CRC remains unclear. This study seeks to elucidate the clinical relevance, biological function, and potential molecular mechanisms of ABHD6 in CRC. We investigated the role of ABHD6 in clinical settings, conducting proliferation, migration, and cell cycle assays. To determine the influence of ABHD6 expression levels on Oxaliplatin sensitivity, we also performed apoptosis assays. RNA sequencing and KEGG analysis were utilized to uncover the potential molecular mechanisms of ABHD6. Furthermore, we validated its expression levels using Western blot and reactive oxygen species (ROS) detection assays. Our results demonstrated that ABHD6 expression in CRC tissues was notably lower compared to adjacent normal tissues. This low expression correlated with a poorer prognosis for CRC patients. Moreover, ABHD6 overexpression impeded CRC cell proliferation and migration while inducing G0/G1 cell cycle arrest. In vivo experiments revealed that downregulation of ABHD6 resulted in an increase in tumor weight and volume. Mechanistically, ABHD6 overexpression inhibited the activation of the AKT signaling pathway and decreased ROS levels in CRC cells, suggesting the role of ABHD6 in CRC progression via the AKT signaling pathway. Our findings demonstrate that ABHD6 functions as a tumor suppressor, primarily by inhibiting the AKT signaling pathway. This role establishes ABHD6 as a promising prognostic biomarker and a potential therapeutic target for CRC patients.
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Affiliation(s)
- Xiaoyu Xiong
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Changjiang Yang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Yiteng Jin
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Rui Zhang
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Shuo Wang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Lin Gan
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Sen Hou
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Yudi Bao
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Zexian Zeng
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Yingjiang Ye
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Zhidong Gao
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
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17
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Cheng M, Nie Y, Song M, Chen F, Yu Y. Forkhead box O proteins: steering the course of stem cell fate. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:7. [PMID: 38466341 DOI: 10.1186/s13619-024-00190-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 02/26/2024] [Indexed: 03/13/2024]
Abstract
Stem cells are pivotal players in the intricate dance of embryonic development, tissue maintenance, and regeneration. Their behavior is delicately balanced between maintaining their pluripotency and differentiating as needed. Disruptions in this balance can lead to a spectrum of diseases, underscoring the importance of unraveling the complex molecular mechanisms that govern stem cell fate. Forkhead box O (FOXO) proteins, a family of transcription factors, are at the heart of this intricate regulation, influencing a myriad of cellular processes such as survival, metabolism, and DNA repair. Their multifaceted role in steering the destiny of stem cells is evident, as they wield influence over self-renewal, quiescence, and lineage-specific differentiation in both embryonic and adult stem cells. This review delves into the structural and regulatory intricacies of FOXO transcription factors, shedding light on their pivotal roles in shaping the fate of stem cells. By providing insights into the specific functions of FOXO in determining stem cell fate, this review aims to pave the way for targeted interventions that could modulate stem cell behavior and potentially revolutionize the treatment and prevention of diseases.
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Affiliation(s)
- Mengdi Cheng
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
| | - Yujie Nie
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
| | - Min Song
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
| | - Fulin Chen
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi, Northwest University, Xi'an, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Yuan Yu
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China.
- Provincial Key Laboratory of Biotechnology of Shaanxi, Northwest University, Xi'an, China.
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China.
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18
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Huo M, Rai SK, Nakatsu K, Deng Y, Jijiwa M. Subverting the Canon: Novel Cancer-Promoting Functions and Mechanisms for snoRNAs. Int J Mol Sci 2024; 25:2923. [PMID: 38474168 PMCID: PMC10932220 DOI: 10.3390/ijms25052923] [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: 01/18/2024] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Small nucleolar RNAs (snoRNAs) constitute a class of intron-derived non-coding RNAs ranging from 60 to 300 nucleotides. Canonically localized in the nucleolus, snoRNAs play a pivotal role in RNA modifications and pre-ribosomal RNA processing. Based on the types of modifications they involve, such as methylation and pseudouridylation, they are classified into two main families-box C/D and H/ACA snoRNAs. Recent investigations have revealed the unconventional synthesis and biogenesis strategies of snoRNAs, indicating their more profound roles in pathogenesis than previously envisioned. This review consolidates recent discoveries surrounding snoRNAs and provides insights into their mechanistic roles in cancer. It explores the intricate interactions of snoRNAs within signaling pathways and speculates on potential therapeutic solutions emerging from snoRNA research. In addition, it presents recent findings on the long non-coding small nucleolar RNA host gene (lncSNHG), a subset of long non-coding RNAs (lncRNAs), which are the transcripts of parental SNHGs that generate snoRNA. The nucleolus, the functional epicenter of snoRNAs, is also discussed. Through a deconstruction of the pathways driving snoRNA-induced oncogenesis, this review aims to serve as a roadmap to guide future research in the nuanced field of snoRNA-cancer interactions and inspire potential snoRNA-related cancer therapies.
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Affiliation(s)
- Matthew Huo
- Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA;
- Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA; (S.K.R.); (K.N.)
| | - Sudhir Kumar Rai
- Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA; (S.K.R.); (K.N.)
| | - Ken Nakatsu
- Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA; (S.K.R.); (K.N.)
- Emory College of Arts and Sciences, Emory University, Atlanta, GA 30322, USA
| | - Youping Deng
- Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA; (S.K.R.); (K.N.)
| | - Mayumi Jijiwa
- Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA; (S.K.R.); (K.N.)
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19
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Ghosh C, Hu J. Importance of targeting various cell signaling pathways in solid cancers. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:101-155. [PMID: 38663958 DOI: 10.1016/bs.ircmb.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Most adult human cancers are solid tumors prevailing in vital organs and lead to mortality all over the globe. Genetic and epigenetic alterations in cancer genes or genes of associated signaling pathways impart the most common characteristic of malignancy, that is, uncontrolled proliferation. Unless the mechanism of action of these cells signaling pathways (involved in cell proliferation, apoptosis, metastasis, and the maintenance of the stemness of cancer stem cells and cancer microenvironment) and their physiologic alteration are extensively studied, it is challenging to understand tumorigenesis as well as develop new treatments and precision medicines. Targeted therapy is one of the most promising strategies for treating various cancers. However, cancer is an evolving disease, and most patients develop resistance to these drugs by acquired mutations or mediation of microenvironmental factors or due to tumor heterogeneity. Researchers are striving to develop novel therapeutic options like combinatorial approaches targeting multiple responsible pathways effectively. Thus, in-depth knowledge of cell signaling and its components remains a critical topic of cancer research. This chapter summarized various extensively studied pathways in solid cancer and how they are targeted for therapeutic strategies.
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Affiliation(s)
- Chandrayee Ghosh
- Department of Surgery, Stanford University, Stanford, CA, Unites States.
| | - Jiangnan Hu
- Department of Surgery, Stanford University, Stanford, CA, Unites States
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20
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Huang X, Zhang M, Zhang Z. The Role of LMP1 in Epstein-Barr Virus-associated Gastric Cancer. Curr Cancer Drug Targets 2024; 24:127-141. [PMID: 37183458 DOI: 10.2174/1568009623666230512153741] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 05/16/2023]
Abstract
EBV promotes many cancers such as lymphoma, nasopharyngeal carcinoma, and gastric; Latent Membrane Protein 1 (LMP1) is considered to be a major oncogenic protein encoded by Epstein- Barr virus (EBV). LMP1 functions as a carcinogen in lymphoma and nasopharyngeal carcinoma, and LMP1 may also promote gastric cancer. The expression level of LMP1 in host cells is a key determinant in tumorigenesis and maintenance of virus specificity. By promoting cell immortalization and cell transformation, promoting cell proliferation, affecting immunity, and regulating cell apoptosis, LMP1 plays a crucial tumorigenic role in epithelial cancers. However, very little is currently known about LMP1 in Epstein-Barr virus-associated gastric cancer (EBVaGC); the main reason is that the expression level of LMP1 in EBVaGC is comparatively lower than other EBV-encoded proteins, such as The Latent Membrane Protein 2A (LMP2A), Epstein-Barr nuclear antigen 1 (EBNA1) and BamHI-A rightward frame 1 (BARF1), to date, there are few studies related to LMP1 in EBVaGC. Recent studies have demonstrated that LMP1 promotes EBVaGC by affecting The phosphatidylinositol 3-kinase- Akt (PI3K-Akt), Nuclear factor-kappa B (NF-κB), and other signaling pathways to regulate many downstream targets such as Forkhead box class O (FOXO), C-X-C-motif chemokine receptor (CXCR), COX-2 (Cyclooxygenase-2); moreover, the gene methylation induced by LMP1 in EBVaGC has become one of the characteristics that distinguish this gastric cancer (GC) from other types of gastric cancer and LMP1 also promotes the formation of the tumor microenvironment (TME) of EBVaGC in several ways. This review synthesizes previous relevant literature, aiming to highlight the latest findings on the mechanism of action of LMP1 in EBVaGC, summarize the function of LMP1 in EBVaGC, lay the theoretical foundation for subsequent new research on LMP1 in EBVaGC, and contribute to the development of novel LMP1-targeted drugs.
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Affiliation(s)
- Xinqi Huang
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Meilan Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Zhiwei Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
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21
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Feng W, Ma C, Rao H, Zhang W, Liu C, Xu Y, Aji R, Wang Z, Xu J, Gao WQ, Li L. Setd2 deficiency promotes gastric tumorigenesis through inhibiting the SIRT1/FOXO pathway. Cancer Lett 2023; 579:216470. [PMID: 37914019 DOI: 10.1016/j.canlet.2023.216470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/19/2023] [Accepted: 10/29/2023] [Indexed: 11/03/2023]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer death globally. SETD2 is a histone methyltransferase catalyzing tri-methylation of H3K36 (H3K36me3) and has been shown to participate in diverse biological processes and human tumors. However, the mechanism of SETD2 in GC remains unclear. Here, we reported that Setd2 deficiency predicts poor prognosis of gastric cancer. SETD2 loss facilitated H. felis/MNU and c-Myc-induced gastric tumorigenesis, respectively. The mouse model of stomach-specific Setd2 depletion together with c-MYC overexpression (AMS) developed high-grade epithelial defects, intestinal metaplasia and dysplasia at only 10-12 weeks of age. Mechanistically, Setd2 depletion resulted in impaired epigenetic regulation of Sirt1, thus inhibiting the SIRT1/FOXO pathway. Moreover, the agonists of FOXO signaling or overexpression of SIRT1 significantly rescued the enhanced cell proliferation and migration caused by Setd2 deficiency in SGC7901 cells. Together, our findings highlight an epigenetic mechanism by which SETD2 regulates gastric tumorigenesis through SIRT1/FOXO pathway. It may also pave the way for the development of targeted, patient-tailored therapies for GC patients with Setd2 deficiency.
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Affiliation(s)
- Wenxin Feng
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Chunxiao Ma
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Hanyu Rao
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Zhang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Changwei Liu
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yue Xu
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Rebiguli Aji
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Ziyi Wang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Jin Xu
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Li Li
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
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22
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Callaway CS, Mouchantat LM, Bitler BG, Bonetto A. Mechanisms of Ovarian Cancer-Associated Cachexia. Endocrinology 2023; 165:bqad176. [PMID: 37980602 PMCID: PMC10699881 DOI: 10.1210/endocr/bqad176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/02/2023] [Accepted: 11/15/2023] [Indexed: 11/21/2023]
Abstract
Cancer-associated cachexia occurs in 50% to 80% of cancer patients and is responsible for 20% to 30% of cancer-related deaths. Cachexia limits survival and treatment outcomes, and is a major contributor to morbidity and mortality during cancer. Ovarian cancer is one of the leading causes of cancer-related deaths in women, and recent studies have begun to highlight the prevalence and clinical impact of cachexia in this population. Here, we review the existing understanding of cachexia pathophysiology and summarize relevant studies assessing ovarian cancer-associated cachexia in clinical and preclinical studies. In clinical studies, there is increased evidence that reduced skeletal muscle mass and quality associate with worse outcomes in subjects with ovarian cancer. Mouse models of ovarian cancer display cachexia, often characterized by muscle and fat wasting alongside inflammation, although they remain underexplored relative to other cachexia-associated cancer types. Certain soluble factors have been identified and successfully targeted in these models, providing novel therapeutic targets for mitigating cachexia during ovarian cancer. However, given the relatively low number of studies, the translational relevance of these findings is yet to be determined and requires more research. Overall, our current understanding of ovarian cancer-associated cachexia is insufficient and this review highlights the need for future research specifically aimed at exploring mechanisms of ovarian cancer-associated cachexia by using unbiased approaches and animal models representative of the clinical landscape of ovarian cancer.
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Affiliation(s)
- Chandler S Callaway
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Lila M Mouchantat
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Benjamin G Bitler
- Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Andrea Bonetto
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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23
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Tsuji-Tamura K, Ogawa M. FOXO1 promotes endothelial cell elongation and angiogenesis by up-regulating the phosphorylation of myosin light chain 2. Angiogenesis 2023; 26:523-545. [PMID: 37488325 DOI: 10.1007/s10456-023-09884-7] [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: 01/06/2023] [Accepted: 07/11/2023] [Indexed: 07/26/2023]
Abstract
The forkhead box O1 (FOXO1) is an important transcription factor related to proliferation, metabolism, and homeostasis, while the major phenotype of FOXO1-null mice is abnormal vascular morphology, such as vessel enlargement and dilation. In in vitro mouse embryonic stem cell (ESC)-differentiation system, Foxo1-/- vascular endothelial cells (ECs) fail to elongate, and mimic the abnormalities of FOXO1-deficiency in vivo. Here, we identified the PPP1R14C gene as the FOXO1 target genes responsible for elongating using transcriptome analyses in ESC-derived ECs (ESC-ECs), and found that the FOXO1-PPP1R14C-myosin light chain 2 (MLC2) axis is required for EC elongation during angiogenesis. MLC2 is phosphorylated by MLC kinase (MLCK) and dephosphorylated by MLC phosphatase (MLCP). PPP1R14C is an inhibitor of PP1, the catalytic subunit of MLCP. The abnormal morphology of Foxo1-/- ESC-ECs was associated with low level of PPP1R14C and loss of MLC2 phosphorylation, which were reversed by PPP1R14C-introduction. Knockdown of either FOXO1 or PPP1R14C suppressed vascular cord formation and reduced MLC2 phosphorylation in human ECs (HUVECs). The mouse and human PPP1R14C locus possesses an enhancer element containing conserved FOXO1-binding motifs. In vivo chemical inhibition of MLC2 phosphorylation caused dilated vascular structures in mouse embryos. Furthermore, foxo1 or ppp1r14c-knockdown zebrafish exhibited vascular malformations, which were also restored by PPP1R14C-introduction. Mechanistically, FOXO1 suppressed MLCP activity by up-regulating PPP1R14C expression, thereby promoting MLC2 phosphorylation and EC elongation, which are necessary for vascular development. Given the importance of MLC2 phosphorylation in cell morphogenesis, this study may provide novel insights into the role of FOXO1 in control of angiogenesis.
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Affiliation(s)
- Kiyomi Tsuji-Tamura
- Oral Biochemistry and Molecular Biology, Department of Oral Health Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-Ku, Sapporo, 060-8586, Japan.
| | - Minetaro Ogawa
- Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
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24
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Santos BF, Grenho I, Martel PJ, Ferreira BI, Link W. FOXO family isoforms. Cell Death Dis 2023; 14:702. [PMID: 37891184 PMCID: PMC10611805 DOI: 10.1038/s41419-023-06177-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 06/30/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023]
Abstract
FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.
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Affiliation(s)
- Bruno F Santos
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Centro Hospitalar Universitário do Algarve (CHUA). Rua Leão Penedo, 8000-386, Faro, Portugal
| | - Inês Grenho
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
| | - Paulo J Martel
- Center for Health Technology and Services Research (CINTESIS)@RISE, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
| | - Bibiana I Ferreira
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM). Arturo Duperier 4, 28029, Madrid, Spain.
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25
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Tabnak P, Hasanzade Bashkandi A, Ebrahimnezhad M, Soleimani M. Forkhead box transcription factors (FOXOs and FOXM1) in glioma: from molecular mechanisms to therapeutics. Cancer Cell Int 2023; 23:238. [PMID: 37821870 PMCID: PMC10568859 DOI: 10.1186/s12935-023-03090-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/04/2023] [Indexed: 10/13/2023] Open
Abstract
Glioma is the most aggressive and malignant type of primary brain tumor, comprises the majority of central nervous system deaths, and is categorized into different subgroups according to its histological characteristics, including astrocytomas, oligodendrogliomas, glioblastoma multiforme (GBM), and mixed tumors. The forkhead box (FOX) transcription factors comprise a collection of proteins that play various roles in numerous complex molecular cascades and have been discovered to be differentially expressed in distinct glioma subtypes. FOXM1 and FOXOs have been recognized as crucial transcription factors in tumor cells, including glioma cells. Accumulating data indicates that FOXM1 acts as an oncogene in various types of cancers, and a significant part of studies has investigated its function in glioma. Although recent studies considered FOXO subgroups as tumor suppressors, there are pieces of evidence that they may have an oncogenic role. This review will discuss the subtle functions of FOXOs and FOXM1 in gliomas, dissecting their regulatory network with other proteins, microRNAs and their role in glioma progression, including stem cell differentiation and therapy resistance/sensitivity, alongside highlighting recent pharmacological progress for modulating their expression.
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Affiliation(s)
- Peyman Tabnak
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Mohammad Ebrahimnezhad
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdieh Soleimani
- Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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26
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Lan J, Wang Y, Yue S, Xu D, Li Y, Peng X, Hu J, Ju E, He S, Li T. Targeting FoxO proteins induces lytic reactivation of KSHV for treating herpesviral primary effusion lymphoma. PLoS Pathog 2023; 19:e1011581. [PMID: 37594999 PMCID: PMC10468091 DOI: 10.1371/journal.ppat.1011581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/30/2023] [Accepted: 07/27/2023] [Indexed: 08/20/2023] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus consisting of both latent and lytic life cycles. Primary effusion lymphoma (PEL) is an aggressive B-cell lineage lymphoma, dominantly latently infected by KSHV. The latent infection of KSHV is persistent and poses an obstacle to killing tumor cells. Like the "shock and kill" strategy designed to eliminate latent HIV reservoir, methods that induce viral lytic reactivation in tumor latently infected by viruses represent a unique antineoplastic strategy, as it could potentially increase the specificity of cytotoxicity in cancer. Inspired by this conception, we proposed that the induction of KSHV lytic reactivation from latency could be a potential therapeutic stratagem for KSHV-associated cancers. Oxidative stress, the clinical hallmark of PEL, is one of the most prominent inducers for KSHV reactivation. Paradoxically, we found that hydrogen peroxide (H2O2) triggers robust cytotoxic effects on KSHV-negative rather than KSHV-positive B lymphoma cells in a dose-dependent manner. Mechanistically, we identified forkhead box protein O1 (FoxO1) and FoxO3 as irrevocable antioxidant defense genes and both of them are upregulated by KSHV latent infection, which is essential for the promoted ROS scavenging in KSHV-positive B lymphoma cells. Pharmacological inhibition or functional knockdown of either FoxO1 or FoxO3 is sufficient to ablate the antioxidant ability and therefore increases the intracellular ROS level that further reverses KSHV from latency to active lytic replication in PEL cells, resulting in tremendous cell death both in vitro and in vivo. Additionally, the elevated level of ROS by inhibiting FoxO proteins further sensitizes PEL cells to ROS-induced apoptosis. Our study therefore demonstrated that the lytic reactivation of KSHV by inhibiting FoxO proteins is a promising therapeutic approach for PEL, which could be further extended to other virus-associated diseases.
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Affiliation(s)
- Jungang Lan
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Yeqing Wang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Shusheng Yue
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Duo Xu
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Yinan Li
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Xiangyu Peng
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Jiao Hu
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Enguo Ju
- Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shanping He
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
| | - Tingting Li
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
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27
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Lees J, Hay J, Moles MW, Michie AM. The discrete roles of individual FOXO transcription factor family members in B-cell malignancies. Front Immunol 2023; 14:1179101. [PMID: 37275916 PMCID: PMC10233034 DOI: 10.3389/fimmu.2023.1179101] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/05/2023] [Indexed: 06/07/2023] Open
Abstract
Forkhead box (FOX) class O (FOXO) proteins are a dynamic family of transcription factors composed of four family members: FOXO1, FOXO3, FOXO4 and FOXO6. As context-dependent transcriptional activators and repressors, the FOXO family regulates diverse cellular processes including cell cycle arrest, apoptosis, metabolism, longevity and cell fate determination. A central pathway responsible for negative regulation of FOXO activity is the phosphatidylinositol-3-kinase (PI3K)-AKT signalling pathway, enabling cell survival and proliferation. FOXO family members can be further regulated by distinct kinases, both positively (e.g., JNK, AMPK) and negatively (e.g., ERK-MAPK, CDK2), with additional post-translational modifications further impacting on FOXO activity. Evidence has suggested that FOXOs behave as 'bona fide' tumour suppressors, through transcriptional programmes regulating several cellular behaviours including cell cycle arrest and apoptosis. However, an alternative paradigm has emerged which indicates that FOXOs operate as mediators of cellular homeostasis and/or resistance in both 'normal' and pathophysiological scenarios. Distinct FOXO family members fulfil discrete roles during normal B cell maturation and function, and it is now clear that FOXOs are aberrantly expressed and mutated in discrete B-cell malignancies. While active FOXO function is generally associated with disease suppression in chronic lymphocytic leukemia for example, FOXO expression is associated with disease progression in diffuse large B cell lymphoma, an observation also seen in other cancers. The opposing functions of the FOXO family drives the debate about the circumstances in which FOXOs favour or hinder disease progression, and whether targeting FOXO-mediated processes would be effective in the treatment of B-cell malignancies. Here, we discuss the disparate roles of FOXO family members in B lineage cells, the regulatory events that influence FOXO function focusing mainly on post-translational modifications, and consider the potential for future development of therapies that target FOXO activity.
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Affiliation(s)
| | | | | | - Alison M. Michie
- Paul O’Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
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28
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Moore XTR, Gheghiani L, Fu Z. The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors. Cells 2023; 12:cells12091344. [PMID: 37174744 PMCID: PMC10177174 DOI: 10.3390/cells12091344] [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: 03/28/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Polo-like kinase 1 (PLK1) is a serine/threonine kinase with more than 600 phosphorylation substrates through which it regulates many biological processes, including mitosis, apoptosis, metabolism, RNA processing, vesicle transport, and G2 DNA-damage checkpoint recovery, among others. Among the many PLK1 targets are members of the FOX family of transcription factors (FOX TFs), including FOXM1, FOXO1, FOXO3, and FOXK1. FOXM1 and FOXK1 have critical oncogenic roles in cancer through their antagonism of apoptotic signals and their promotion of cell proliferation, metastasis, angiogenesis, and therapeutic resistance. In contrast, FOXO1 and FOXO3 have been identified to have broad functions in maintaining cellular homeostasis. In this review, we discuss PLK1-mediated regulation of FOX TFs, highlighting the effects of PLK1 on the activity and stability of these proteins. In addition, we review the prognostic and clinical significance of these proteins in human cancers and, more importantly, the different approaches that have been used to disrupt PLK1 and FOX TF-mediated signaling networks. Furthermore, we discuss the therapeutic potential of targeting PLK1-regulated FOX TFs in human cancers.
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Affiliation(s)
- Xavier T R Moore
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Lilia Gheghiani
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Zheng Fu
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
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29
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Bai H, Fang CW, Shi Y, Zhai S, Jiang A, Li YN, Wang L, Liu QL, Zhou GY, Cao JH, Li J, Yang XK, Qin XJ. Mitochondria-derived H2O2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice. Cell Death Dis 2023; 14:216. [PMID: 36977674 PMCID: PMC10050396 DOI: 10.1038/s41419-023-05744-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023]
Abstract
AbstractReactive oxygen species (ROS) can induce oxidative injury and are generally regarded as toxic byproducts, although they are increasingly recognized for their signaling functions. Increased ROS often accompanies liver regeneration (LR) after liver injuries, however, their role in LR and the underlying mechanism remains unclear. Here, by employing a mouse LR model of partial hepatectomy (PHx), we found that PHx induced rapid increases of mitochondrial hydrogen peroxide (H2O2) and intracellular H2O2 at an early stage, using a mitochondria-specific probe. Scavenging mitochondrial H2O2 in mice with liver-specific overexpression of mitochondria-targeted catalase (mCAT) decreased intracellular H2O2 and compromised LR, while NADPH oxidases (NOXs) inhibition did not affect intracellular H2O2 or LR, indicating that mitochondria-derived H2O2 played an essential role in LR after PHx. Furthermore, pharmacological activation of FoxO3a impaired the H2O2-triggered LR, while liver-specific knockdown of FoxO3a by CRISPR-Cas9 technology almost abolished the inhibition of LR by overexpression of mCAT, demonstrating that FoxO3a signaling pathway mediated mitochondria-derived H2O2 triggered LR after PHx. Our findings uncover the beneficial roles of mitochondrial H2O2 and the redox-regulated underlying mechanisms during LR, which shed light on potential therapeutic interventions for LR-related liver injury. Importantly, these findings also indicate that improper antioxidative intervention might impair LR and delay the recovery of LR-related diseases in clinics.
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30
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Rani M, Kumari R, Singh SP, Devi A, Bansal P, Siddiqi A, Alsahli MA, Almatroodi SA, Rahmani AH, Rizvi MMA. MicroRNAs as master regulators of FOXO transcription factors in cancer management. Life Sci 2023; 321:121535. [PMID: 36906255 DOI: 10.1016/j.lfs.2023.121535] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/19/2023] [Accepted: 02/23/2023] [Indexed: 03/12/2023]
Abstract
MicroRNAs are critical regulators of the plethora of genes, including FOXO "forkhead" dependent transcription factors, which are bonafide tumour suppressors. The FOXO family members modulate a hub of cellular processes like apoptosis, cell cycle arrest, differentiation, ROS detoxification, and longevity. Aberrant expression of FOXOs in human cancers has been observed due to their down-regulation by diverse microRNAs, which are predominantly involved in tumour initiation, chemo-resistance and tumour progression. Chemo-resistance is a major obstacle in cancer treatment. Over 90% of casualties in cancer patients are reportedly associated with chemo-resistance. Here, we have primarily discussed the structure, functions of FOXO and also their post-translational modifications which influence the activities of these FOXO family members. Further, we have addressed the role of microRNAs in carcinogenesis by regulating the FOXOs at post-transcriptional level. Therefore, microRNAs-FOXO axis can be exploited as a novel cancer therapy. The administration of microRNA-based cancer therapy is likely to be beneficial to curb chemo-resistance in cancers.
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Affiliation(s)
- Madhu Rani
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Rashmi Kumari
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Shashi Prakash Singh
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India; Centre for Pharmacology and Therapeutics, Rosewell Park Comprehensive Care Centre, 665 Elm Street, Buffalo, NY, USA 14203
| | - Annu Devi
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
| | - Preeti Bansal
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Aisha Siddiqi
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Mohammed A Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Buraydah 51452, Saudi Arabia
| | - Saleh A Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Buraydah 51452, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Buraydah 51452, Saudi Arabia
| | - M Moshahid Alam Rizvi
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India.
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31
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Li T, Gao SJ. KSHV hijacks FoxO1 to promote cell proliferation and cellular transformation by antagonizing oxidative stress. J Med Virol 2023; 95:e28676. [PMID: 36929740 PMCID: PMC10285692 DOI: 10.1002/jmv.28676] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023]
Abstract
Reactive oxygen species (ROS) are a group of a highly short-lived molecules that control diverse behaviors of cells. Normal cells maintain ROS balance to ensure their functions. Because of oncogenic stress, cancer cells often have excessive ROS, also known as oxidative stress, which are often counteracted by enhanced antioxidant systems to maintain redox homeostasis. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with Kaposi's sarcoma (KS), which manifests hyper inflammation and oxidative stress as the hallmarks. We have previously shown that excessive ROS can disrupt KSHV latency by inducing viral lytic replication, leading to cell death. Paradoxically, most KS tumor cells are latently infected by KSHV in a highly inflammatory and oxidative stress tumor microenvironment, which is in part due to the activation of alternative complement and TLR4 pathways, indicating the existence of an enhanced antioxidant defense system in KS tumor cells. In this study, we show that KSHV upregulates antioxidant genes, including SOD2 and CAT by hijacking the forkhead box protein O1 (FoxO1), to maintain intracellular ROS level. Moreover, the fine-tuned balance of ROS level in KSHV-transformed cells is essential for cell survival. Consequently, KSHV-transformed cells are extremely sensitive to exogenous ROS insult such as treatment with a low level of hydrogen peroxide (H2 O2 ). Either chemical inhibition or knockdown of FoxO1 by short interfering RNAs decreases the expression of antioxidant genes and subsequently increases the intracellular ROS level in KSHV-transformed cells, resulting in the inhibition of cell proliferation and colony formation in soft agar. Mechanistically, KSHV-encoded microRNAs and vFLIP upregulate FoxO1 by activating the NF-κB pathway. These results reveal a novel mechanism by which an oncogenic virus counteracts oxidative stress by upregulating FoxO1, which is essential for KSHV-induced cell proliferation and cellular transformation. Therefore, FoxO1 might be a potential therapeutic target for KSHV-related malignancies.
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Affiliation(s)
- Tingting Li
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Current address: Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, China
| | - Shou-Jiang Gao
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Flores D, Lopez A, Udawant S, Gunn B, Keniry M. The FOXO1 inhibitor AS1842856 triggers apoptosis in glioblastoma multiforme and basal-like breast cancer cells. FEBS Open Bio 2023; 13:352-362. [PMID: 36602390 PMCID: PMC9900086 DOI: 10.1002/2211-5463.13547] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 01/06/2023] Open
Abstract
Basal-like breast cancer (BBC) and glioblastoma multiforme (GBM) are poor-prognosis cancers that lack effective targeted therapies and harbor embryonic stem gene expression signatures. Recently, our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 (a cell-permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block transcriptional regulation) on BBC and GBM cell viability. We treated a set of BBC and GBM cancer cell lines with increasing concentrations of AS1842856 and found reduced colony formation. Treatment of BBC and GBM cancer cells with AS1842856 led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide. Treatment with another FOXO1 inhibitor AS1708727 or FOXO1 RNAi also led to FAS induction. This work is the first to show that targeting BBC and GBM with FOXO1 inhibition leads to apoptosis. These novel findings may ultimately expand the repertoire of therapies for poor-prognosis cancers.
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Affiliation(s)
- David Flores
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Alma Lopez
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Shreya Udawant
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Bonnie Gunn
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
| | - Megan Keniry
- Department of BiologyUniversity of Texas‐Rio Grande ValleyEdinburgTXUSA
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Shi P, Ruan Y, Liu W, Sun J, Xu J, Xu H. Analysis of Promoter Methylation of the Bovine FOXO1 Gene and Its Effect on Proliferation and Differentiation of Myoblasts. Animals (Basel) 2023; 13:ani13020319. [PMID: 36670858 PMCID: PMC9854826 DOI: 10.3390/ani13020319] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/01/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
This study aimed to explore the regulatory role of FOXO1 promoter methylation on its transcriptional level and unravel the effect of FOXO1 on the proliferation and differentiation of bovine myoblasts. Bisulfite sequencing polymerase chain reaction (BSP) and real-time quantitative PCR were performed to determine the methylation status and transcript levels of the FOXO1 promoter region at different growth stages. BSP results showed that the methylation level in the calf bovine (CB) group was significantly higher than that in the adult bovine (AB) group (p < 0.05). On the other hand, qRT-PCR results indicated that the mRNA expression level in the AB group was significantly higher than that in the CB group (p < 0.05), suggesting a significant decrease in gene expression at high levels of DNA methylation. CCK-8 and flow cytometry were applied to determine the effect of silencing the FOXO1 gene on the proliferation of bovine myoblasts. Furthermore, qRT-PCR and Western blot were conducted to analyze the expression of genes associated with the proliferation and differentiation of bovine myoblasts. Results from CCK-8 revealed that the short hairpin FOXO1 (shFOXO1) group significantly promoted the proliferation of myoblasts compared to the short-hairpin negative control (shNC) group (p < 0.05). Flow cytometry results showed a significant decrease in the number of the G1 phase cells (p < 0.05) and a significant increase in the number of the S phase cells (p < 0.05) in the shFOXO1 group compared to the shNC group. In addition, the expression of key genes for myoblast proliferation (CDK2, PCNA, and CCND1) and differentiation (MYOG, MYOD, and MYHC) was significantly increased at both mRNA and protein levels (p < 0.05). In summary, this study has demonstrated that FOXO1 transcription is regulated by methylation in the promoter region and that silencing FOXO1 promotes the proliferation and differentiation of bovine myoblasts. Overall, our findings lay the foundation for further studies on the regulatory role of epigenetics in the development of bovine myoblasts.
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Affiliation(s)
- Pengfei Shi
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Yong Ruan
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Wenjiao Liu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Jinkui Sun
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
| | - Jiali Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
| | - Houqiang Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China
- College of Animal Science, Guizhou University, Guiyang 550025, China
- Correspondence:
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Xie J, Zhang J, Tian W, Zou Y, Tang Y, Zheng S, Wong CW, Deng X, Wu S, Chen J, Mo Y, Xie X. The Pan-Cancer Multi-Omics Landscape of FOXO Family Relevant to Clinical Outcome and Drug Resistance. Int J Mol Sci 2022; 23:ijms232415647. [PMID: 36555288 PMCID: PMC9778770 DOI: 10.3390/ijms232415647] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
The forkhead box O (FOXO) transcription factors (TFs) family are frequently mutated, deleted, or amplified in various human cancers, making them attractive candidates for therapy. However, their roles in pan-cancer remain unclear. Here, we evaluated the expression, prognostic value, mutation, methylation, and clinical features of four FOXO family genes (FOXO1, FOXO3, FOXO4, and FOXO6) in 33 types of cancers based on the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. We used a single sample gene set enrichment analysis (ssGSEA) algorithm to establish a novel index called "FOXOs score". Moreover, we investigated the association between the FOXOs score and tumor microenvironment (TME), the responses to multiple treatments, along with drug resistance. We found that the FOXO family genes participated in tumor progression and were related to the prognosis in various types of cancer. We calculated the FOXOs score and found that it was significantly correlated with multiple malignant pathways in pan-cancer, including Wnt/beta-catenin signaling, TGF-beta signaling, and hedgehog signaling. In addition, the FOXOs score was also associated with multiple immune-related characteristics. Furthermore, the FOXOs score was sensitive for predicting the efficacy of diverse treatments in multiple cancers, especially immunotherapy. In conclusion, FOXO family genes were vital in pan-cancer and were strongly correlated with the TME. A high FOXOs score indicated an excellent immune-activated TME and sensitivity to multiple treatments. Hence, the FOXOs score might potentially be used as a biomarker in patients with a tumor.
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Affiliation(s)
- Jindong Xie
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Junsheng Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wenwen Tian
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yutian Zou
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yuhui Tang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Shaoquan Zheng
- Breast Disease Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510060, China
| | - Chau-Wei Wong
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Xinpei Deng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Song Wu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Junxin Chen
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510060, China
| | - Yunxian Mo
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Correspondence: (Y.M.); (X.X.); Tel.: +86-13924277788 (X.X.); Fax: +86-20-87343805 (X.X.)
| | - Xiaoming Xie
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Correspondence: (Y.M.); (X.X.); Tel.: +86-13924277788 (X.X.); Fax: +86-20-87343805 (X.X.)
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Jagosky MH, Anderson CJ, Symanowski JT, Steuerwald NM, Farhangfar CJ, Baldrige EA, Benbow JH, Livingston MB, Patt JC, Ahrens WA, Kneisl JS, Kim ES. Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma. Cancer Med 2022; 12:7029-7038. [PMID: 36464833 PMCID: PMC10067084 DOI: 10.1002/cam4.5502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/20/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Patients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options. EXPERIMENTAL DESIGN Patients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes. RESULTS Thirty-eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow-up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%-29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease-specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090). CONCLUSIONS This is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications.
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Affiliation(s)
- Megan H. Jagosky
- Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Colin J. Anderson
- Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health Charlotte North Carolina USA
| | - James T. Symanowski
- Department of Biostatistics, Levine Cancer Institute, Carolinas Medical Center Atrium Health Charlotte North Carolina USA
| | - Nury M. Steuerwald
- The Molecular Biology and Genomics Laboratory, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Carol J. Farhangfar
- LCI Translational Research, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Emily A. Baldrige
- LCI Research Support, Clinical Trials Office, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | | | - Michael B. Livingston
- Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Joshua C. Patt
- Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health Charlotte North Carolina USA
| | - Will A. Ahrens
- Department of Pathology Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Jeffrey S. Kneisl
- Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health Charlotte North Carolina USA
| | - Edward S. Kim
- City of Hope Comprehensive Cancer Center Duarte California USA
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Ladke VS, Kumbhar GM, Joshi K, Kheur S. Systemic explanation of Glycyrrhiza glabra's analyzed compounds and anti-cancer mechanism based on network pharmacology in oral cancer. J Oral Biosci 2022; 64:452-460. [PMID: 36113760 DOI: 10.1016/j.job.2022.09.002] [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: 07/12/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVES Several studies suggest that Glycyrrhiza glabra (GG) extract could be a useful supplemental source for various cancer treatments. However, very few studies on oral cancer (OC) have been conducted. The present study was aimed at exploring the bioactive compounds (bioactives) along with the mode of action of GG against OC using network pharmacology. METHODS Liquid chromatography-mass spectrometry/mass spectrometry was used to identify and analyze compounds from GG. Public databases were used to identify genes associated with the selected bioactives and OC. With the help of Cytoscape software, the association between bioactive and common genes was built, visualized, and investigated. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to investigate protein-protein interactions for intergenic interactions. Finally, the pathway enrichment analysis of common genes was done using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. RESULTS Overall, 378 bioactives were identified in GG. Using public databases, an entire 254 bioactive-related genes and 734 OC-related genes were recognized, with 48 common genes. Cytoscape analysis showed wortmannin as the key bioactive and androgen receptor as the hub gene. The DAVID results revealed that the significant mechanism of action of GG against OC may be to induce apoptosis of cancer cells by deactivating the PI3K-AKT signaling pathway. CONCLUSION The key active components and mechanisms of action of GG against OC were investigated. The present study provides scientific suggestions to support the clinical outcome of GG for OC along with a research foundation for additional elaboration on the important bioactives and mechanisms of GG against OC.
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Affiliation(s)
- Vaibhav S Ladke
- Interdisciplinary School of Health Sciences, SPPU, India; Research Associate, Central Research Facility, Dr. D. Y. Patil Medical College, Hospital and Research Center, India.
| | - Gauri M Kumbhar
- Research Associate, Central Research Facility, Dr. D. Y. Patil Medical College, Hospital and Research Center, India.
| | - Kalpana Joshi
- Department of Biotechnology, Sinhgad College of Engineering, India.
| | - Supriya Kheur
- Research Associate, Central Research Facility, Dr. D. Y. Patil Medical College, Hospital and Research Center, India.
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Jin H, Kim HJ. P2Y2R-Mediated PAK1 Activation Is Involved in ESM-1 Overexpression in RT-R-MDA-MB-231 through FoxO1 Regulation. Cancers (Basel) 2022; 14:cancers14174124. [PMID: 36077661 PMCID: PMC9454712 DOI: 10.3390/cancers14174124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/08/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
ESM-1, overexpressed in several cancer types, is a potential cancer diagnostic and prognostic indicator. In our previous study, we determined that RT-R-TNBC cells were more aggressive than TNBC cells, and this difference was associated with ESM-1 overexpression. However, the mechanism explaining upregulated ESM-1 expression in RT-R-TNBC cells compared to TNBC cells was unclear. Therefore, we aimed to identify the mechanism by which ESM-1 is overexpressed in RT-R-MDA-MB-231 cells. RT-R-MDA-MB-231 cells were treated with various ESM-1 transcription factor inhibitors, and only the FoxO1 inhibitor downregulated ESM-1 expression. FoxO1 nuclear localization was modulated by JNK and p38 MAPKs, which were differentially regulated by PKC, PDK1 and PAK1. PAK1 profoundly modulated JNK and p38 MAPKs, whereas PKC and PDK1 affected only p38 MAPK. P2Y2R activated by ATP, which is highly released from RT-R-BC cells, was involved in PAK1 activation, subsequent JNK and p38 MAPK activation, FoxO1 induction, and ESM-1 expression in RT-R-MDA-MB-231 cells. These findings suggest for the first time that ESM-1 was overexpressed in RT-R-MDA-MB-231 cells and regulated through the P2Y2R-PAK1-FoxO1 signaling pathway.
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Affiliation(s)
- Hana Jin
- Department of Pharmacology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Korea
| | - Hye Jung Kim
- Department of Pharmacology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Korea
- Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 52727, Korea
- Correspondence: ; Tel.: +82-55-772-8074
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Mathivanan S, Chunchagatta Lakshman PK, Singh M, Giridharan S, Sathish K, Hurakadli MA, Bharatham K, Kamariah N. Structure of a 14-3-3ε:FOXO3a pS253 Phosphopeptide Complex Reveals 14-3-3 Isoform-Specific Binding of Forkhead Box Class O Transcription Factor (FOXO) Phosphoproteins. ACS OMEGA 2022; 7:24344-24352. [PMID: 35874228 PMCID: PMC9301721 DOI: 10.1021/acsomega.2c01700] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The transcriptional activity of Forkhead Box O3 (FOXO3a) is inactivated by AKT-mediated phosphorylation on Serine 253 (S253), which enables FOXO3a binding to 14-3-3. Phosphorylated FOXO3a binding to 14-3-3 facilitates the nuclear exclusion of FOXO3a, causing cancer cell proliferation. The FOXO3a/14-3-3 interaction has, therefore, emerged as an important therapeutic target. Here, we report a comprehensive analysis using fluorescence polarization, isothermal titration calorimetry, small-angle X-ray scattering, X-ray crystallography, and molecular dynamics simulations to gain molecular-level insights into the interaction of FOXO3apS253 phosphopeptide with 14-3-3ε. A high-resolution structure of the fluorophore-labeled FOXO3apS253:14-3-3ε complex revealed a distinct mode of interaction compared to other 14-3-3 phosphopeptide complexes. FOXO3apS253 phosphopeptide showed significant structural difference in the positions of the -3 and -4 Arg residues relative to pSer, compared to that of a similar phosphopeptide, FOXO1pS256 bound to 14-3-3σ. Moreover, molecular dynamics studies show that the significant structural changes and molecular interactions noticed in the crystal structure of FOXO3apS253:14-3-3ε are preserved over the course of the simulation. Thus, this study reveals structural differences between the binding to 14-3-3 isoforms of FOXO1pS256 versus FOXO3apS253, providing a framework for the rational design of isoform-specific FOXO/14-3-3 protein-protein interaction inhibitors for therapy.
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Hall DCN, Benndorf RA. Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited. Cell Mol Life Sci 2022; 79:393. [PMID: 35780223 PMCID: PMC9250486 DOI: 10.1007/s00018-022-04430-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/01/2022] [Accepted: 06/14/2022] [Indexed: 11/30/2022]
Abstract
PIK3CA mutations are amongst the most prevalent somatic mutations in cancer and are associated with resistance to first-line treatment along with low survival rates in a variety of malignancies. There is evidence that patients carrying PIK3CA mutations may benefit from treatment with acetylsalicylic acid, commonly known as aspirin, particularly in the setting of colorectal cancer. In this regard, it has been clarified that Class IA Phosphatidylinositol 3-kinases (PI3K), whose catalytic subunit p110α is encoded by the PIK3CA gene, are involved in signal transduction that regulates cell cycle, cell growth, and metabolism and, if disturbed, induces carcinogenic effects. Although PI3K is associated with pro-inflammatory cyclooxygenase-2 (COX-2) expression and signaling, and COX-2 is among the best-studied targets of aspirin, the mechanisms behind this clinically relevant phenomenon are still unclear. Indeed, there is further evidence that the protective, anti-carcinogenic effect of aspirin in this setting may be mediated in a COX-independent manner. However, until now the understanding of aspirin's prostaglandin-independent mode of action is poor. This review will provide an overview of the current literature on this topic and aims to analyze possible mechanisms and targets behind the aspirin sensitivity of PIK3CA-mutated cancers.
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Affiliation(s)
- Daniella C N Hall
- Department of Clinical Pharmacy and Pharmacotherapy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle (Saale), Germany
| | - Ralf A Benndorf
- Department of Clinical Pharmacy and Pharmacotherapy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle (Saale), Germany.
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The FOXO family of transcription factors: key molecular players in gastric cancer. J Mol Med (Berl) 2022; 100:997-1015. [PMID: 35680690 DOI: 10.1007/s00109-022-02219-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/19/2022] [Accepted: 06/01/2022] [Indexed: 10/18/2022]
Abstract
Gastric cancer (GC) is the fifth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related death with an oncological origin. Despite its decline in incidence and mortality in recent years, GC remains a global public problem that seriously threatens patients' health and lives. The forkhead box O proteins (FOXOs) are a family of evolutionarily conserved transcription factors (TFs) with crucial roles in cell fate decisions. In mammals, the FOXO family consists of four members FOXO1, 3a, 4, and 6. FOXOs play crucial roles in a variety of biological processes, such as development, metabolism, and stem cell maintenance, by regulating the expression of their target genes in space and time. An accumulating amount of evidence has shown that the dysregulation of FOXOs is involved in GC progression by affecting multiple cellular processes, including proliferation, apoptosis, invasion, metastasis, cell cycle progression, carcinogenesis, and resistance to chemotherapeutic drugs. In this review, we systematically summarize the recent findings on the regulatory mechanisms of FOXO family expression and activity and elucidate its roles in GC progression. Moreover, we also highlight the clinical implications of FOXOs in GC treatment.
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Downregulated Copper Homeostasis-Related Gene FOXO1 as a Novel Indicator for the Prognosis and Immune Response of Breast Cancer. J Immunol Res 2022; 2022:9140461. [PMID: 35800988 PMCID: PMC9256448 DOI: 10.1155/2022/9140461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/02/2022] [Indexed: 11/17/2022] Open
Abstract
Copper (Cu) is one of the essential microelements for all living systems. Studies have illustrated the biological significance of Cu homeostasis in human cancers, including breast cancer (BRCA). Nevertheless, the detailed roles of Cu homeostasis in BRCA need to be further explored. Here, we identified a downregulated Cu homeostasis-related gene FOXO1 and investigated the potential functions of FOXO1 in BRCA through several bioinformation databases. The BRCA patients with high level of FOXO1 displayed favorable prognostic values. Subsequently, enrichment analysis of FOXO1 coexpressed genes revealed that the top three enriched KEGG pathways were spliceosome, oxidative phosphorylation, and ribosome. Immunoinfiltration analysis indicated that aberrantly expressed FOXO1 showed positive correlations with the subcellular infiltration of macrophages and neutrophils in BRCA. Moreover, FOXO1 expression was positively associated with multiple immune checkpoints, such as sialic acid-binding immunoglobulin-like lectin 15 (SIGLEC15), indoleamine 2,3-dioxygenase 1 (IDO1), programmed cell death 1 ligand 1 (PD-L1/CD274), hepatitis A virus cellular receptor 2 (HAVCR2), programmed cell death 1 (PDCD1), cytotoxic T lymphocyte antigen 4 (CTLA4), and programmed cell death 1 ligand 2 (PDCD1LG2). Overall, these findings would deepen our understanding of FOXO1 in BRCA prognosis and immunotherapy response, representing a promising therapeutic strategy for BRCA patients.
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Zhao S, Wu Y, Wei Y, Xu X, Zheng J. Identification of Biomarkers Associated With CD8+ T Cells in Coronary Artery Disease and Their Pan-Cancer Analysis. Front Immunol 2022; 13:876616. [PMID: 35799780 PMCID: PMC9254733 DOI: 10.3389/fimmu.2022.876616] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/24/2022] [Indexed: 11/13/2022] Open
Abstract
PurposeTo identify biomarkers associated with CD8+ T cells in coronary artery disease (CAD) and initially explore their potential role in the tumor immune microenvironment.Materials and MethodsCAD-related datasets GSE12288, GSE34198, and GSE66360, were downloaded from the GEO database. First, GSVA was performed based on the GSE12288 dataset. Then WGCNA analysis was performed to identify the most relevant module and candidate hub gene for CD8+ T cells, followed by GO and KEGG analysis of this module. Secondly, the relationship between candidate hub genes and CD8+ T cells was verified using GSE34198 and GSE66360, which led to the identification of hub genes. The relationship of hub genes with CD8+ T cells in cancer was analyzed using the TIMER database. Methylation analysis of hub genes was performed using the DiseaseMeth database. CAD, pan-cancer, pan-cell lines, and pan-normal tissues, correlations between hub genes. In addition, potential drugs and TFs associated with hub genes were predicted, and the ceRNA network was constructed. Finally, GSEA was performed separately for hub genes.ResultsCAD was shown to be associated with immune response by GSVA analysis. WGCNA identified the blue module as most related to CD8+ T cells and identified nine candidate hub genes. The relevance of CAD to immunity was further confirmed by GO and KEGG analysis of the module. Two additional datasets validated and identified three hub genes (FBXO7, RAD23A, and MKRN1) that significantly correlated with CD8+ T cells. In addition, we found that hub genes were positively associated with CD8+ T cells in TGCT, THCA, and KICH cancers by our analysis. Moreover, the hub gene was differentially methylated. We also analyzed the correlation between hub genes in CAD, different cancers, different cell lines, and different normal tissues. The results of all the analyses showed a positive correlation between them. Finally, we successfully constructed hub gene-associated TF-gene and ceRNA networks and predicted 11 drugs associated with hub genes. GSEA suggests that hub genes are related to multiple immune response processes.ConclusionFBXO7, RAD23A, and MKRN1 are significantly associated with CD8+ T cells in CAD and multiple cancers and may act through immune responses in CAD and cancer.
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Affiliation(s)
- Shijian Zhao
- Department of Cardiology, the Affiliated Cardiovascular Hospital of Kunming Medical University (Fuwai Yunnan Cardiovascular Hospital), Kunming, China
| | - Yinteng Wu
- Department of Orthopedic and Trauma Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Yantao Wei
- Department of Cardiology, the Affiliated Cardiovascular Hospital of Kunming Medical University (Fuwai Yunnan Cardiovascular Hospital), Kunming, China
| | - Xiaoyu Xu
- Department of Cardiology, the Affiliated Cardiovascular Hospital of Kunming Medical University (Fuwai Yunnan Cardiovascular Hospital), Kunming, China
| | - Jialin Zheng
- Department of Cardiology, the Affiliated Cardiovascular Hospital of Kunming Medical University (Fuwai Yunnan Cardiovascular Hospital), Kunming, China
- *Correspondence: Jialin Zheng,
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Sahoo SS, Ramanand SG, Gao Y, Abbas A, Kumar A, Cuevas IC, Li HD, Aguilar M, Xing C, Mani RS, Castrillon DH. FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity. J Clin Invest 2022; 132:157574. [PMID: 35703180 PMCID: PMC9197528 DOI: 10.1172/jci157574] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/04/2022] [Indexed: 01/23/2023] Open
Abstract
FOXA2 encodes a transcription factor mutated in 10% of endometrial cancers (ECs), with a higher mutation rate in aggressive variants. FOXA2 has essential roles in embryonic and uterine development. However, FOXA2’s role in EC is incompletely understood. Functional investigations using human and mouse EC cell lines revealed that FOXA2 controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and endometrial-epithelial transition. In live animals, conditional inactivation of Foxa2 or Pten alone in endometrial epithelium did not result in ECs, but simultaneous inactivation of both genes resulted in lethal ECs with complete penetrance, establishing potent synergism between Foxa2 and PI3K signaling. Studies in tumor-derived cell lines and organoids highlighted additional invasion and cell growth phenotypes associated with malignant transformation and identified key mediators, including Myc and Cdh1. Transcriptome and cistrome analyses revealed that FOXA2 broadly controls gene expression programs through modification of enhancer activity in addition to regulating specific target genes, rationalizing its tumor suppressor functions. By integrating results from our cell lines, organoids, animal models, and patient data, our findings demonstrated that FOXA2 is an endometrial tumor suppressor associated with aggressive disease and with shared commonalities among its roles in endometrial function and carcinogenesis.
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Affiliation(s)
| | | | | | | | - Ashwani Kumar
- Eugene McDermott Center for Human Growth and Development
| | | | | | | | - Chao Xing
- Eugene McDermott Center for Human Growth and Development.,Department of Bioinformatics.,Department of Population and Data Sciences
| | - Ram S Mani
- Department of Pathology.,Harold C. Simmons Comprehensive Cancer Center.,Department of Urology, and
| | - Diego H Castrillon
- Department of Pathology.,Harold C. Simmons Comprehensive Cancer Center.,Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas, Texas, USA
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Wang C, Liang H, Li Y, Tang Z, Zhang Y. Chemokine (C-C motif) ligand 18/membrane-associated 3/forkhead box O1 axis promotes the proliferation, migration, and invasion of intrahepatic cholangiocarcinoma. Bioengineered 2022; 13:12738-12748. [PMID: 35609322 PMCID: PMC9276021 DOI: 10.1080/21655979.2022.2069383] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Phosphatidylinositol Transfer Protein, Membrane-Associated 3 (PITPNM3) often bind with chemokine (C-C motif) ligand 18 (CCL18) to promote tumor progression. However, the role of PITPNM3 in intrahepatic cholangiocarcinoma (ICC) is unclear. We first searched GEPIA database and detected the PITPNM3 expression using immunohistochemistry and real-time quantitative PCR. The results showed that PITPNM3 is high expression in ICC tissues and cells. Then we investigated the cell function of CLL18 and PITPNM3 through cell clone formation assay and transwell assay. The results indicated that CCL18 treatment promoted the proliferation, migration, and invasion of ICC cells. Silence of PITPNM3 reversed the effect of CCL18 on cell function. Simultaneously, we detected key protein expression of forkhead box O1 (FOXO1) and nuclear factor kappa B (NF-KB) through western blotting and found that CCL18 activated NF-KB pathway while inhibited FOXO1 pathway, the effect of which were attenuated by silence of PITPNM3. Finally, we confirmed which pathway affected the cell function using inhibitor of FOXO1 (AS1842856) and activator of NF-KB (Asatone). The results showed that AS1842856, not Asatone, relieved the inhibitory effect of si-PITPNM3 on the cell function of CCL18. In short, CCL18 treatment activated PITPNM3 to promote the proliferation, migration, and invasion of ICC via FOXO1 signaling pathway. These results provided a new insight for the diagnosis and therapy of ICC.
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Affiliation(s)
- Chusi Wang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hao Liang
- Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanjie Li
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhaofeng Tang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Zhong Q, Liu Y, Correa MR, Marconett CN, Minoo P, Li C, Ann DK, Zhou B, Borok Z. FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells. Cells 2022; 11:1122. [PMID: 35406686 PMCID: PMC8997990 DOI: 10.3390/cells11071122] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 02/03/2023] Open
Abstract
NKX2.1 is a master regulator of lung morphogenesis and cell specification; however, interactions of NKX2.1 with various transcription factors to regulate cell-specific gene expression and cell fate in the distal lung remain incompletely understood. FOXO1 is a key regulator of stem/progenitor cell maintenance/differentiation in several tissues but its role in the regulation of lung alveolar epithelial progenitor homeostasis has not been evaluated. We identified a novel role for FOXO1 in alveolar epithelial cell (AEC) differentiation that results in the removal of NKX2.1 from surfactant gene promoters and the subsequent loss of surfactant expression in alveolar epithelial type I-like (AT1-like) cells. We found that the FOXO1 forkhead domain potentiates a loss of surfactant gene expression through an interaction with the NKX2.1 homeodomain, disrupting NKX2.1 binding to the SFTPC promoter. In addition, blocking PI-3K/AKT signaling reduces phosphorylated FOXO-1 (p-FOXO1), allowing accumulated nuclear FOXO1 to interact with NKX2.1 in differentiating AEC. Inhibiting AEC differentiation in vitro with keratinocyte growth factor (KGF) maintained an AT2 cell phenotype through increased PI3K/AKT-mediated FOXO1 phosphorylation, resulting in higher levels of surfactant expression. Together these results indicate that FOXO1 plays a central role in AEC differentiation by directly binding NKX2.1 and suggests an essential role for FOXO1 in mediating AEC homeostasis.
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Affiliation(s)
- Qian Zhong
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (Q.Z.); (Y.L.)
| | - Yixin Liu
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (Q.Z.); (Y.L.)
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (M.R.C.); (C.N.M.); (P.M.); (C.L.)
| | - Michele Ramos Correa
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (M.R.C.); (C.N.M.); (P.M.); (C.L.)
- USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Crystal Nicole Marconett
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (M.R.C.); (C.N.M.); (P.M.); (C.L.)
- USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Parviz Minoo
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (M.R.C.); (C.N.M.); (P.M.); (C.L.)
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Changgong Li
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (M.R.C.); (C.N.M.); (P.M.); (C.L.)
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - David K. Ann
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA;
| | - Beiyun Zhou
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (Q.Z.); (Y.L.)
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (M.R.C.); (C.N.M.); (P.M.); (C.L.)
- USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Zea Borok
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (M.R.C.); (C.N.M.); (P.M.); (C.L.)
- USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, CA 92037, USA
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Deng S, Leong HC, Datta A, Gopal V, Kumar AP, Yap CT. PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression. Cancers (Basel) 2022; 14:1652. [PMID: 35406424 PMCID: PMC8997157 DOI: 10.3390/cancers14071652] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/13/2022] [Accepted: 03/21/2022] [Indexed: 02/01/2023] Open
Abstract
The PI3K/AKT signaling pathway plays essential roles in multiple cellular processes, which include cell growth, survival, metabolism, and motility. In response to internal and external stimuli, the PI3K/AKT signaling pathway co-opts other signaling pathways, cellular components, and cytoskeletal proteins to reshape individual cells. The cytoskeletal network comprises three main components, which are namely the microfilaments, microtubules, and intermediate filaments. Collectively, they are essential for many fundamental structures and cellular processes. In cancer, aberrant activation of the PI3K/AKT signaling cascade and alteration of cytoskeletal structures have been observed to be highly prevalent, and eventually contribute to many cancer hallmarks. Due to their critical roles in tumor progression, pharmacological agents targeting PI3K/AKT, along with cytoskeletal components, have been developed for better intervention strategies against cancer. In our review, we first discuss existing evidence in-depth and then build on recent advances to propose new directions for therapeutic intervention.
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Affiliation(s)
- Shuo Deng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (S.D.); (V.G.)
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
| | - Hin Chong Leong
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
- Departments of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Arpita Datta
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
| | - Vennila Gopal
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (S.D.); (V.G.)
| | - Alan Prem Kumar
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore;
- Departments of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
| | - Celestial T. Yap
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (S.D.); (V.G.)
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
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Fusi L, Paudel R, Meder K, Schlosser A, Schrama D, Goebeler M, Schmidt M. Interaction of transcription factor FoxO3 with histone acetyltransferase complex subunit TRRAP Modulates Gene Expression and Apoptosis. J Biol Chem 2022; 298:101714. [PMID: 35151693 PMCID: PMC8914384 DOI: 10.1016/j.jbc.2022.101714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/28/2021] [Accepted: 01/19/2022] [Indexed: 11/01/2022] Open
Abstract
Forkhead box O (FoxO) transcription factors are conserved proteins involved in the regulation of life span and age-related diseases, such as diabetes and cancer. Stress stimuli or growth factor deprivation promotes nuclear localization and activation of FoxO proteins, which—depending on the cellular context—can lead to cell cycle arrest or apoptosis. In endothelial cells (ECs), they further regulate angiogenesis and may promote inflammation and vessel destabilization implicating a role of FoxOs in vascular diseases. In several cancers, FoxOs exert a tumor-suppressive function by regulating proliferation and survival. We and others have previously shown that FoxOs can regulate these processes via two different mechanisms: by direct binding to forkhead-responsive elements at the promoter of target genes or by a poorly understood alternative process that does not require direct DNA binding and regulates key targets in primary human ECs. Here, we performed an interaction study in ECs to identify new nuclear FoxO3 interaction partners that might contribute to FoxO-dependent gene regulation. Mass spectrometry analysis of FoxO3-interacting proteins revealed transformation/transcription domain–associated protein (TRRAP), a member of multiple histone acetyltransferase complexes, as a novel binding partner of FoxO family proteins. We demonstrate that TRRAP is required to support FoxO3 transactivation and FoxO3-dependent G1 arrest and apoptosis in ECs via transcriptional activation of the cyclin-dependent kinase inhibitor p27kip1 and the proapoptotic B-cell lymphoma 2 family member, BIM. Moreover, FoxO–TRRAP interaction could explain FoxO-induced alternative gene regulation via TRRAP-dependent recruitment to target promoters lacking forkhead-responsive element sequences.
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van der Ploeg P, Uittenboogaard A, Bosch SL, van Diest PJ, Wesseling-Rozendaal YJ, van de Stolpe A, Lambrechts S, Bekkers RL, Piek JM. Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium. Gynecol Oncol 2022; 165:114-120. [DOI: 10.1016/j.ygyno.2022.01.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 01/14/2022] [Accepted: 01/24/2022] [Indexed: 01/23/2023]
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Chen Y, Zhao H, Liang W, Jiang E, Zhou X, Shao Z, Liu K, Shang Z. Autophagy regulates the cancer stem cell phenotype of head and neck squamous cell carcinoma through the noncanonical FOXO3/SOX2 axis. Oncogene 2022; 41:634-646. [PMID: 34795388 PMCID: PMC8799462 DOI: 10.1038/s41388-021-02115-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 11/01/2021] [Accepted: 11/04/2021] [Indexed: 12/12/2022]
Abstract
Autophagy is an essential catabolic process that orchestrates cellular homeostasis and plays dual roles in tumor promotion and suppression. However, the mechanism by which autophagy affects the self-renewal of cancer stem cells (CSCs) remains unclear. In this study, we investigated whether autophagy activation contributes to CSC properties of head and neck squamous cell carcinoma (HNSCC). The results showed that the autophagy level and CSC properties of HNSCC cells were elevated in response to several adverse conditions, including treatment with cisplatin, starvation, and hypoxia. Pretreatment with autophagy inhibitors, such as 3-MA and chloroquine, diminished the CSC properties acquired under adverse conditions. In addition, the isolated CSCs were endowed with stronger autophagic activity than non-CSCs, and the CSC properties were dampened when autophagy was inhibited either by 3-MA, chloroquine, or Beclin1 knockdown. Notably, the tumor-initiating activity of CSCs was decreased upon knocking down Beclin1. Further study revealed that FOXO3, a substrate for autophagy, was enriched in the nucleus of cells with lower autophagy levels. Nuclear FOXO3 directly bound to the promoter region of SOX2 and negatively regulated its transcriptional activity. Overexpression of FOXO3 decreased the expression of SOX2 and thereby impaired the CSC phenotype both in vitro and in vivo. Taken together, our findings suggest that the activation of autophagy is essential for the acquisition of CSC properties in adverse conditions and the self-renewal of CSCs. We clarify the role of autophagy in regulating the CSC phenotype and demonstrate that the noncanonical FOXO3/SOX2 axis is the intrinsic regulatory mechanism.
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Affiliation(s)
- Yang Chen
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China
| | - Hui Zhao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China
| | - Weilian Liang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China
| | - Erhui Jiang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xiaocheng Zhou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhe Shao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ke Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhengjun Shang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China.
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
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He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, Li B. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6:425. [PMID: 34916492 PMCID: PMC8677728 DOI: 10.1038/s41392-021-00828-5] [Citation(s) in RCA: 658] [Impact Index Per Article: 164.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 11/02/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.
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Affiliation(s)
- Yan He
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Miao Miao Sun
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou, China
| | - Guo Geng Zhang
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Jing Yang
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Kui Sheng Chen
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou, China.
| | - Wen Wen Xu
- MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
| | - Bin Li
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
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