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Affiliation(s)
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1
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Mivehchi H, Eskandari-Yaghbastlo A, Emrahoglu S, Saeidpour Masouleh S, Faghihinia F, Ayoubi S, Nabi Afjadi M. Tiny messengers, big Impact: Exosomes driving EMT in oral cancer. Pathol Res Pract 2025; 268:155873. [PMID: 40022766 DOI: 10.1016/j.prp.2025.155873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/13/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
Exosomes are indispensable extracellular vesicles that facilitate intercellular communication and are crucial for both healthy and pathological conditions, including cancer. The capacity of exosomes to echo the molecular characteristics of their cells of origin, including malignant cells, makes them indispensable tools for diagnosing and tracking disease progression in the field of oncology. Oral squamous cell carcinoma (OSCC), which has been identified as the sixth most prevalent cancer worldwide, has been linked to numerous risk factors, including tobacco use, alcohol consumption, human papillomavirus (HPV) infection, and inadequate oral hygiene. Exosomes pointedly influence the advancement of oral cancer via promoting tumor cell growth, invasion, angiogenesis, and immune evasion through the alteration of the tumor microenvironment. A critical apparatus in cancer metastasis is the epithelial-to-mesenchymal transition (EMT), during which cancer cells acquire improved migratory and invasive properties. EMT plays a role in metastasis, resistance to treatment, and evasion of the immune response. Exosomes facilitate EMT in oral cancer by delivering bioactive molecules that influence EMT signaling pathways. These exosomes inspire EMT in recipient cells, by this means enhancing tumor invasion and metastasis. This study aims to identify the specific exosomal components and signaling pathways that are tangled in EMT, in that way providing new avenues for targeted therapies designed to hinder the metastasis of oral cancer.
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Affiliation(s)
- Hassan Mivehchi
- Faculty of Dentistry, University of Debrecen, Debrecen, Hungary
| | | | - Sahand Emrahoglu
- School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA
| | | | - Farbod Faghihinia
- School of Dentistry, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Saminalsadat Ayoubi
- School of Dental Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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2
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Lusby R, Demirdizen E, Inayatullah M, Kundu P, Maiques O, Zhang Z, Terp MG, Sanz-Moreno V, Tiwari VK. Pan-cancer drivers of metastasis. Mol Cancer 2025; 24:2. [PMID: 39748426 PMCID: PMC11697158 DOI: 10.1186/s12943-024-02182-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/22/2024] [Indexed: 01/04/2025] Open
Abstract
Metastasis remains a leading cause of cancer-related mortality, irrespective of the primary tumour origin. However, the core gene regulatory program governing distinct stages of metastasis across cancers remains poorly understood. We investigate this through single-cell transcriptome analysis encompassing over two hundred patients with metastatic and non-metastatic tumours across six cancer types. Our analysis revealed a prognostic core gene signature that provides insights into the intricate cellular dynamics and gene regulatory networks driving metastasis progression at the pan-cancer and single-cell level. Notably, the dissection of transcription factor networks active across different stages of metastasis, combined with functional perturbation, identified SP1 and KLF5 as key regulators, acting as drivers and suppressors of metastasis, respectively, at critical steps of this transition across multiple cancer types. Through in vivo and in vitro loss of function of SP1 in cancer cells, we revealed its role in driving cancer cell survival, invasive growth, and metastatic colonisation. Furthermore, tumour cells and the microenvironment increasingly engage in communication through WNT signalling as metastasis progresses, driven by SP1. Further validating these observations, a drug repurposing analysis identified distinct FDA-approved drugs with anti-metastasis properties, including inhibitors of WNT signalling across various cancers.
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Affiliation(s)
- Ryan Lusby
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast, Belfast, BT9 7BL, UK
| | - Engin Demirdizen
- Institute for Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark
| | - Mohammed Inayatullah
- Institute for Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark
| | - Paramita Kundu
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
| | - Oscar Maiques
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
| | - Ziyi Zhang
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast, Belfast, BT9 7BL, UK
| | - Mikkel Green Terp
- Institute for Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark
| | - Victoria Sanz-Moreno
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London, EC1M 6BQ, UK
| | - Vijay K Tiwari
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast, Belfast, BT9 7BL, UK.
- Institute for Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
- Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, BT9 7AE, Belfast, UK.
- Danish Institute for Advanced Study (DIAS), University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
- Department of Clinical Genetics, Odense University Hospital, 5000, Odense C, Denmark.
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3
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Duan X, Xing Z, Qiao L, Qin S, Zhao X, Gong Y, Li X. The role of histone post-translational modifications in cancer and cancer immunity: functions, mechanisms and therapeutic implications. Front Immunol 2024; 15:1495221. [PMID: 39620228 PMCID: PMC11604627 DOI: 10.3389/fimmu.2024.1495221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 10/18/2024] [Indexed: 12/11/2024] Open
Abstract
Histones play crucial roles in both promoting and repressing gene expression, primarily regulated through post-translational modifications (PTMs) at specific amino acid residues. Histone PTMs, including methylation, acetylation, ubiquitination, phosphorylation, lactylation, butyrylation, and propionylation, act as important epigenetic markers. These modifications influence not only chromatin compaction but also gene expression. Their importance extends to the treatment and prevention of various human diseases, particularly cancer, due to their involvement in key cellular processes. Abnormal histone modifications and the enzymes responsible for these alterations often serve as critical drivers in tumor cell proliferation, invasion, apoptosis, and stemness. This review introduces key histone PTMs and the enzymes responsible for these modifications, examining their impact on tumorigenesis and cancer progression. Furthermore, it explores therapeutic strategies targeting histone PTMs and offers recommendations for identifying new potential therapeutic targets.
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Affiliation(s)
- Xiaohong Duan
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Zhiyao Xing
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
| | - Lu Qiao
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Shan Qin
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xuejing Zhao
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Yanhua Gong
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xueren Li
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
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4
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Li C, Kaur A, Pavlidaki A, Spenlé C, Rajnpreht I, Donnadieu E, Salomé N, Molitor A, Carapito R, Wack F, Erne W, Lefebvre O, Averous G, Mitrentsi I, Loustau T, Orend G. Targeting the MAtrix REgulating MOtif abolishes several hallmarks of cancer, triggering antitumor immunity. Proc Natl Acad Sci U S A 2024; 121:e2404485121. [PMID: 39382998 PMCID: PMC11494334 DOI: 10.1073/pnas.2404485121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/26/2024] [Indexed: 10/11/2024] Open
Abstract
Tumor-targeted therapies have often been inefficient due to the lack of concomitant control over the tumor microenvironment. Using an immunocompetent autologous breast cancer model, we investigated a MAtrix REgulating MOtif (MAREMO)-mimicking peptide, which inhibits the protumorigenic extracellular matrix (ECM) molecule tenascin-C that activates several cancer hallmarks. In cultured cells, targeting the MAREMO blocks tenascin-C signaling involved in cell adhesion and immune-suppression by inhibiting tenascin-C interactions with fibronectin, TGFβ, CXCL12, and others, thereby blocking downstream events. Using RNASequencing and various genetic, molecular, in situ, and in vivo assays, we demonstrate that the MAREMO peptide similarly blocks multiple tenascin-C functions in vivo. This includes releasing tumor-infiltrating leukocytes, including CD8+ T cells, from the stroma. The MAREMO peptide also triggers interferon signaling, restoring antitumor immunity, contributing to tumor growth inhibition and reduced dissemination. The MAREMO peptide targets tumor cells directly by promoting growth suppression and inhibiting phenotypic plasticity, subsequently enhancing responsiveness to the endogenous death inducer tumor necrosis factor-related apoptosis-inducing ligand, as shown by a loss-of-function approach. Moreover, the MAREMO peptide largely subdues the tumor bed by depleting fibroblasts, repressing tenascin-C and other ECM molecules, and restoring the function of the few remaining blood vessels. In conclusion, targeting tenascin-C with a MAREMO peptide represents a powerful anticancer strategy with a broad inhibition of several cancer hallmarks.
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Affiliation(s)
- Chengbei Li
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
| | - Amanpreet Kaur
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
| | - Alexia Pavlidaki
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
| | - Caroline Spenlé
- École Supérieure de Biotechnologie de Strasbourg (ESBS) UMR 7242, Groupe Peptide Thérapeutique, University of Strasbourg, Illkirch67400, France
| | - Irena Rajnpreht
- Université Paris Cité, CNRS, Inserm, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris75014, France
| | - Emmanuel Donnadieu
- Université Paris Cité, CNRS, Inserm, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris75014, France
| | - Nathalie Salomé
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
| | - Anne Molitor
- University of Strasbourg, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
- Laboratoire d’ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Plateforme GENOMAX, Institut Thématique Interdisciplinaire de Médecine de Précision de Strasbourg, Transplantex Next Generation (NG), Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Strasbourg67091, France
| | - Raphael Carapito
- University of Strasbourg, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
- Laboratoire d’ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Plateforme GENOMAX, Institut Thématique Interdisciplinaire de Médecine de Précision de Strasbourg, Transplantex Next Generation (NG), Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Strasbourg67091, France
| | - Fanny Wack
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
| | - William Erne
- University of Strasbourg, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
- INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg67091, France
| | - Olivier Lefebvre
- University of Strasbourg, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
- INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg67091, France
| | - Gerlinde Averous
- Département de Pathologie, University Hospital Strasbourg, Strasbourg67200, France
| | - Ioanna Mitrentsi
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
| | - Thomas Loustau
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
- University of Strasbourg, Institut Universitaire Technologique (IUT) Louis Pasteur, Schiltigheim67300, France
| | - Gertraud Orend
- University of Strasbourg, Strasbourg67091, France
- INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d’Hématologie et d’Immunologie, Strasbourg67091, France
- Fédération de Médecine Translationnelle de Strasbourg, Strasbourg67091, France
- INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg67091, France
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Johansen AM, Forsythe SD, McGrath CT, Barker G, Jimenez H, Paluri RK, Pasche BC. TGFβ in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance. Clin Cancer Res 2024; 30:3676-3687. [PMID: 38916900 PMCID: PMC11371528 DOI: 10.1158/1078-0432.ccr-24-0468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/16/2024] [Accepted: 05/30/2024] [Indexed: 06/26/2024]
Abstract
TGFβ is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.
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Affiliation(s)
- Allan M. Johansen
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Steven D. Forsythe
- Neuroendocrine Therapy Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Callum T. McGrath
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Grayson Barker
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Hugo Jimenez
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
| | - Ravi K. Paluri
- Section of Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082. USA
| | - Boris C. Pasche
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
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Roy SK, Srivastava S, McCance C, Shrivastava A, Morvant J, Shankar S, Srivastava RK. Clinical significance of PNO1 as a novel biomarker and therapeutic target of hepatocellular carcinoma. J Cell Mol Med 2024; 28:e18295. [PMID: 38722284 PMCID: PMC11081011 DOI: 10.1111/jcmm.18295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/10/2024] [Accepted: 03/25/2024] [Indexed: 05/12/2024] Open
Abstract
The RNA-binding protein PNO1 plays an essential role in ribosome biogenesis. Recent studies have shown that it is involved in tumorigenesis; however, its role in hepatocellular carcinoma (HCC) is not well understood. The purpose of this study was to examine whether PNO1 can be used as a biomarker of HCC and also examine the therapeutic potential of PNO1 knockout for the treatment of HCC. PNO1 expression was upregulated in HCC and associated with poor prognosis. PNO1 expression was positively associated with tumour stage, lymph node metastasis and poor survival. PNO1 expression was significantly higher in HCC compared to that in fibrolamellar carcinoma or normal tissues. Furthermore, HCC tissues with mutant Tp53 expressed higher PNO1 than those with wild-type Tp53. PNO1 knockout suppressed cell viability, colony formation and EMT of HCC cells. Since activation of Notch signalling pathway promotes HCC, we measured the effects of PNO1 knockout on the components of Notch pathway and its targets. PNO1 knockout suppressed Notch signalling by modulating the expression of Notch ligands and their receptors, and downstream targets. PNO1 knockout also inhibited genes involved in surface adhesion, cell cycle, inflammation and chemotaxis. PNO1 knockout also inhibited colony and spheroid formation, cell migration and invasion, and markers of stem cells, pluripotency and EMT in CSCs. Overall, our data suggest that PNO1 can be used as a diagnostic and prognostic biomarker of HCC, and knockout of PNO1 by CRISPR/Cas9 can be beneficial for the management of HCC by targeting CSCs.
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Affiliation(s)
- Sanjit K. Roy
- Stanley S. Scott Cancer Center, School of MedicineLouisiana State University HealthNew OrleansLouisianaUSA
| | | | - Caroline McCance
- Department of Cellular and Molecular BiologyTulane UniversityNew OrleansLouisianaUSA
| | | | - Jason Morvant
- Department of SurgeryOchsner Health SystemGretnaLouisianaUSA
| | - Sharmila Shankar
- Southeast Louisiana Veterans Health Care SystemNew OrleansLouisianaUSA
- John W. Deming Department of MedicineTulane University School of MedicineNew OrleansLouisianaUSA
| | - Rakesh K. Srivastava
- Stanley S. Scott Cancer Center, School of MedicineLouisiana State University HealthNew OrleansLouisianaUSA
- Southeast Louisiana Veterans Health Care SystemNew OrleansLouisianaUSA
- Department of GeneticsLouisiana State University Health Sciences Center – New OrleansNew OrleansLouisianaUSA
- GLAXDoverDelawareUSA
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Yang Y, Ma B, Djamshidi M, Zhang Q, Sarkar A, Chanda A, Tran U, Soh J, Sandall C, Chen HM, MacDonald JA, Bonni S, Sensen CW, Zheng J, Riabowol K. ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat. Eur J Cell Biol 2023; 102:151341. [PMID: 37459799 DOI: 10.1016/j.ejcb.2023.151341] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/28/2023] [Accepted: 07/06/2023] [Indexed: 09/22/2023] Open
Abstract
ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find that ING1 knockdown increases expression of Twist1, Zeb 1&2, Snai1, Bmi1 and TSHZ1 drivers of EMT, promoting EMT and cell motility. ING1 expression had the opposite effect, promoting epithelial cell morphology and inhibiting basal and TGF-β-induced motility in 3D organoid cultures. ING1 binds the Twist1 promoter and Twist1 was largely responsible for the ability of ING1 to reduce cell migration. Consistent with ING1 inhibiting Twist1 expression in vivo, an inverse relationship between ING1 and Twist1 levels was seen in breast cancer samples from The Cancer Genome Atlas (TCGA). The HDAC inhibitor vorinostat is approved for treatment of multiple myeloma and cutaneous T cell lymphoma and is in clinical trials for solid tumours as adjuvant therapy. One molecular target of vorinostat is INhibitor of Growth 2 (ING2), that together with ING1 serve as targeting subunits of the Sin3a HDAC complex. Treatment with sublethal (LD25-LD50) levels of vorinostat promoted breast cancer cell migration several-fold, which increased further upon ING1 knockout. These observations indicate that correct targeting of the Sin3a HDAC complex, and HDAC activity in general decreases luminal and basal breast cancer cell motility, suggesting that use of HDAC inhibitors as adjuvant therapies in breast cancers that are prone to metastasize may not be optimal and requires further investigation.
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Affiliation(s)
- Yang Yang
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, PR China
| | - Biao Ma
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, PR China
| | - Mahbod Djamshidi
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Qingrun Zhang
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Anusi Sarkar
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Ayan Chanda
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Uyen Tran
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Jung Soh
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Christina Sandall
- Libin Cardiovascular Institute of Alberta, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Huey-Miin Chen
- Libin Cardiovascular Institute of Alberta, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Justin A MacDonald
- Libin Cardiovascular Institute of Alberta, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Shirin Bonni
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada
| | | | - Jianhua Zheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, PR China
| | - Karl Riabowol
- Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada.
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Farani MR, Sarlak M, Gholami A, Azaraian M, Binabaj MM, Kakavandi S, Tambuwala MM, Taheriazam A, Hashemi M, Ghasemi S. Epigenetic drugs as new emerging therapeutics: What is the scale's orientation of application and challenges? Pathol Res Pract 2023; 248:154688. [PMID: 37494800 DOI: 10.1016/j.prp.2023.154688] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/13/2023] [Accepted: 07/13/2023] [Indexed: 07/28/2023]
Abstract
Epigenetics is the study of heritable changes in gene expression or function without altering the DNA sequence. Important factors are part of epigenetic events, such as methylation, DNA histone rearrangements, nucleosome transposition, and non-coding RNAs. Dysregulated epigenetic mechanics are associated with various cancers' initiation, development, and metastasis. It is known that the occurrence and development of cancer can be controlled by regulating unexpected epigenetic events. Epi-drugs are used singly or in combination with chemotherapy and enhance antitumor activity, reduce drug resistance, and stimulate the host immune response. Despite these benefits, epigenetic therapy as a single therapy or in combination with other drugs leads to adverse effects. This review article introduces and compares the advantages, disadvantages, and side effects of using these drugs for the first time since their introduction. Also, this article describes the mechanism of action of various epigenetic drugs. Recommendations for future use of epigenetic drugs as cancer therapeutics are suggested as an overall conclusion.
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Affiliation(s)
- Marzieh Ramezani Farani
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), the Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, 1417614411 Tehran, Iran
| | - Maryam Sarlak
- Department of Chemistry, Portland State University, Portland, OR, USA
| | - Amir Gholami
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Maryam Azaraian
- Department of Radiology, Charité - Universitätsmedizin Berlin, Berlin 10117, Germany; Department of Bioanalytical Ecotoxicology, UFZ - Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Maryam Moradi Binabaj
- Clinical Biochemistry, Department of Biochemistry and Nutrition, School of Medicine, Sabzevar University of Medical Science, Sabzevar, Iran; Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Sareh Kakavandi
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool, Lincoln, LN6 7TS, 0United Kingdom
| | - Afshin Taheriazam
- Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Sorayya Ghasemi
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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9
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Bhat SM, Prasad PR, Joshi MB. Novel insights into DNA methylation-based epigenetic regulation of breast tumor angiogenesis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 380:63-96. [PMID: 37657860 DOI: 10.1016/bs.ircmb.2023.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
Breast tumors are highly vascularized and dependent on angiogenesis for growth, progression and metastasis. Like other solid tumors, vasculature in breast tumors also display leaky and tortuous phenotype and hence inhibit immune cell infiltration, show reduced efficacy to anticancer drugs and radiotherapy. Epigenetic reprogramming including significant alterations in DNA methylation in tumor and stromal cells generate an imbalance in expression of pro- and anti-angiogenic factors and subsequently lead to disordered angiogenesis. Hence, understanding DNA methylation-based regulation of angiogenesis in breast tumors may open new avenues for designing therapeutic targets. Our present review manuscript summarized contemporary knowledge of influence of DNA methylation in regulating angiogenesis. Further, we identified novel set of pro-angiogenic genes enriched in endothelial cells which are coregulated with DNMT isoforms in breast tumors and harboring CpG islands. Our analysis revealed promoters of pro-angiogenic genes were hypomethylated and anti-angiogenic genes were hypermethylated in tumors and further reflected on their expression patterns. Interestingly, promoter DNA methylation intensities of novel set of pro-angiogenic genes significantly correlated to patient survival outcome.
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Affiliation(s)
- Sharath Mohan Bhat
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Palla Ranga Prasad
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Manjunath B Joshi
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India.
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10
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Roy SK, Srivastava S, Hancock A, Shrivastava A, Morvant J, Shankar S, Srivastava RK. Inhibition of ribosome assembly factor PNO1 by CRISPR/Cas9 technique suppresses lung adenocarcinoma and Notch pathway: Clinical application. J Cell Mol Med 2023; 27:365-378. [PMID: 36625087 PMCID: PMC9889701 DOI: 10.1111/jcmm.17657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/11/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
Growth is crucially controlled by the functional ribosomes available in cells. To meet the enhanced energy demand, cancer cells re-wire and increase their ribosome biogenesis. The RNA-binding protein PNO1, a ribosome assembly factor, plays an essential role in ribosome biogenesis. The purpose of this study was to examine whether PNO1 can be used as a biomarker for lung adenocarcinoma and also examine the molecular mechanisms by which PNO1 knockdown by CRISPR/Cas9 inhibited growth and epithelial-mesenchymal transition (EMT). The expression of PNO1 was significantly higher in lung adenocarcinoma compared to normal lung tissues. PNO1 expression in lung adenocarcinoma patients increased with stage, nodal metastasis, and smoking. Lung adenocarcinoma tissues from males expressed higher PNO1 than those from females. Furthermore, lung adenocarcinoma tissues with mutant Tp53 expressed higher PNO1 than those with wild-type Tp53, suggesting the influence of Tp53 status on PNO1 expression. PNO1 knockdown inhibited cell viability, colony formation, and EMT, and induced apoptosis. Since dysregulated signalling through the Notch receptors promotes lung adenocarcinoma, we measured the effects of PNO1 inhibition on the Notch pathway. PNO1 knockdown inhibited Notch signalling by suppressing the expression of Notch receptors, their ligands, and downstream targets. PNO1 knockdown also suppressed CCND1, p21, PTGS-2, IL-1α, IL-8, and CXCL-8 genes. Overall, our data suggest that PNO1 can be used as a diagnostic biomarker, and also can be an attractive therapeutic target for the treatment of lung adenocarcinoma.
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Affiliation(s)
- Sanjit K. Roy
- Louisiana State University Health‐New Orleans, School of MedicineStanley S. Scott Cancer CenterNew OrleansLouisianaUSA,Southeast Louisiana Veterans Health Care SystemNew OrleansLouisianaUSA
| | | | - Andrew Hancock
- Department of Molecular and Cellular BiologyTulane UniversityNew OrleansLouisianaUSA
| | | | - Jason Morvant
- Department of SurgeryOchsner Health SystemGretnaLouisianaUSA
| | - Sharmila Shankar
- Louisiana State University Health‐New Orleans, School of MedicineStanley S. Scott Cancer CenterNew OrleansLouisianaUSA,Southeast Louisiana Veterans Health Care SystemNew OrleansLouisianaUSA,Department of GeneticsLouisiana State University Health Sciences CenterNew OrleansLouisianaUSA,John W. Deming Department of MedicineTulane University School of MedicineNew OrleansLouisianaUSA,Kansas City VA Medical CenterKansas CityMissouriUSA
| | - Rakesh K. Srivastava
- Louisiana State University Health‐New Orleans, School of MedicineStanley S. Scott Cancer CenterNew OrleansLouisianaUSA,Southeast Louisiana Veterans Health Care SystemNew OrleansLouisianaUSA,Department of GeneticsLouisiana State University Health Sciences CenterNew OrleansLouisianaUSA,Kansas City VA Medical CenterKansas CityMissouriUSA
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11
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Namwan N, Senawong G, Phaosiri C, Kumboonma P, Somsakeesit LO, Samankul A, Leerat C, Senawong T. HDAC Inhibitory and Anti-Cancer Activities of Curcumin and Curcumin Derivative CU17 against Human Lung Cancer A549 Cells. Molecules 2022; 27:4014. [PMID: 35807258 PMCID: PMC9268269 DOI: 10.3390/molecules27134014] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/19/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Previous research reported that the curcumin derivative (CU17) inhibited several cancer cell growths in vitro. However, its anticancer potential against human lung cancer cells (A549 cell lines) has not yet been evaluated. The purpose of this research was to examine the HDAC inhibitory and anti-cancer activities of CU17 compared to curcumin (CU) in A549 cells. An in vitro study showed that CU17 had greater HDAC inhibitory activity than CU. CU17 inhibited HDAC activity in a dose dependent manner with the half-maximal inhibitory concentration (IC50) value of 0.30 ± 0.086 µg/mL against HDAC enzymes from HeLa nuclear extract. In addition, CU17 could bind at the active pockets of both human class I HDACs (HDAC1, 2, 3, and 8) and class II HDACs (HDAC4, 6, and 7) demonstrated by molecular docking studies, and caused hyperacetylation of histone H3 (Ac-H3) in A549 cells shown by Western blot analysis. MTT assay indicated that both CU and CU17 suppressed A549 cell growth in a dose- and time-dependent manner. Besides, CU and CU17 induced G2/M phase cell cycle arrest and p53-independent apoptosis in A549 cells. Both CU and CU17 down-regulated the expression of p53, p21, Bcl-2, and pERK1/2, but up-regulated Bax expression in this cell line. Although CU17 inhibited the growth of lung cancer cells less effectively than CU, it showed less toxicity than CU for non-cancer cells. Accordingly, CU17 is a promising agent for lung cancer treatment. Additionally, CU17 synergized the antiproliferative activity of Gem in A549 cells, indicating the possibility of employing CU17 as an adjuvant treatment to enhance the chemotherapeutic effect of Gem in lung cancer.
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Affiliation(s)
- Narissara Namwan
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand; (N.N.); (G.S.); (A.S.); (C.L.)
| | - Gulsiri Senawong
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand; (N.N.); (G.S.); (A.S.); (C.L.)
| | - Chanokbhorn Phaosiri
- Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Pakit Kumboonma
- Department of Applied Chemistry, Faculty of Science and Liberal Arts, Rajamangala University of Technology Isan, Nakhon Ratchasima 30000, Thailand;
| | - La-or Somsakeesit
- Department of Chemistry, Faculty of Engineering, Rajamangala University of Technology Isan, Khon Kaen 40000, Thailand;
| | - Arunta Samankul
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand; (N.N.); (G.S.); (A.S.); (C.L.)
| | - Chadaporn Leerat
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand; (N.N.); (G.S.); (A.S.); (C.L.)
| | - Thanaset Senawong
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand; (N.N.); (G.S.); (A.S.); (C.L.)
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12
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Kong F, Ma L, Wang X, You H, Zheng K, Tang R. Regulation of epithelial-mesenchymal transition by protein lysine acetylation. Cell Commun Signal 2022; 20:57. [PMID: 35484625 PMCID: PMC9052664 DOI: 10.1186/s12964-022-00870-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/20/2022] [Indexed: 01/01/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a vital driver of tumor progression. It is a well-known and complex trans-differentiation process in which epithelial cells undergo morphogenetic changes with loss of apical-basal polarity, but acquire spindle-shaped mesenchymal phenotypes. Lysine acetylation is a type of protein modification that favors reversibly altering the structure and function of target molecules via the modulation of lysine acetyltransferases (KATs), as well as lysine deacetylases (KDACs). To date, research has found that histones and non-histone proteins can be acetylated to facilitate EMT. Interestingly, histone acetylation is a type of epigenetic regulation that is capable of modulating the acetylation levels of distinct histones at the promoters of EMT-related markers, EMT-inducing transcription factors (EMT-TFs), and EMT-related long non-coding RNAs to control EMT. However, non-histone acetylation is a post-translational modification, and its effect on EMT mainly relies on modulating the acetylation of EMT marker proteins, EMT-TFs, and EMT-related signal transduction molecules. In addition, several inhibitors against KATs and KDACs have been developed, some of which can suppress the development of different cancers by targeting EMT. In this review, we discuss the complex biological roles and molecular mechanisms underlying histone acetylation and non-histone protein acetylation in the control of EMT, highlighting lysine acetylation as potential strategy for the treatment of cancer through the regulation of EMT.
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Video Abstract
- Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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- Lihong Ma
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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- Xing Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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- Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.,National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
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- Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China. .,National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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13
Shen F, Zhuang S. Histone Acetylation and Modifiers in Renal Fibrosis.
Front Pharmacol 2022;
13:760308. [PMID:
35559244 PMCID:
PMC9086452 DOI:
10.3389/fphar.2022.760308]
[Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/04/2022] [Indexed: 12/23/2022] Open
Abstract
Histones are the most abundant proteins bound to DNA in eukaryotic cells and frequently subjected to post-modifications such as acetylation, methylation, phosphorylation and ubiquitination. Many studies have shown that histone modifications, especially histone acetylation, play an important role in the development and progression of renal fibrosis. Histone acetylation is regulated by three families of proteins, including histone acetyltransferases (HATs), histone deacetylases (HDACs) and bromodomain and extraterminal (BET) proteins. These acetylation modifiers are involved in a variety of pathophysiological processes leading to the development of renal fibrosis, including partial epithelial-mesenchymal transition, renal fibroblast activation, inflammatory response, and the expression of pro-fibrosis factors. In this review, we summarize the role and regulatory mechanisms of HATs, HDACs and BET proteins in renal fibrosis and provide evidence for targeting these modifiers to treat various chronic fibrotic kidney diseases in animal models.
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Affiliation(s)
- Fengchen Shen
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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- Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, United States
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14
The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer.
Healthcare (Basel) 2022;
10:healthcare10030557. [PMID:
35327035 PMCID:
PMC8953111 DOI:
10.3390/healthcare10030557]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/06/2022] [Accepted: 03/14/2022] [Indexed: 12/21/2022] Open
Abstract
von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities.
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15
Wang F, Ding Y, Lei X, Liao B, Wu FX. Identifying Gene Signatures for Cancer Drug Repositioning Based on Sample Clustering.
IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2022;
19:953-965. [PMID:
32845842 DOI:
10.1109/tcbb.2020.3019781]
[Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Drug repositioning is an important approach for drug discovery. Computational drug repositioning approaches typically use a gene signature to represent a particular disease and connect the gene signature with drug perturbation profiles. Although disease samples, especially from cancer, may be heterogeneous, most existing methods consider them as a homogeneous set to identify differentially expressed genes (DEGs)for further determining a gene signature. As a result, some genes that should be in a gene signature may be averaged off. In this study, we propose a new framework to identify gene signatures for cancer drug repositioning based on sample clustering (GS4CDRSC). GS4CDRSC first groups samples into several clusters based on their gene expression profiles. Second, an existing method is applied to the samples in each cluster for generating a list of DEGs. Then a weighting approach is used to identify an intergrated gene signature from all the lists of DEGs. The integrated gene signature is used to connect with drug perturbation profiles in the Connectivity Map (CMap)database to generate a list of drug candidates. GS4CDRSC has been tested with several cancer datasets and existing methods. The computational results show that GS4CDRSC outperforms those methods without the sample clustering and weighting approaches in terms of both number and rate of predicted known drugs for specific cancers.
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16
Oliveira T, Hermann E, Lin D, Chowanadisai W, Hull E, Montgomery M. HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells.
Redox Biol 2021;
47:102149. [PMID:
34600336 PMCID:
PMC8487084 DOI:
10.1016/j.redox.2021.102149]
[Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/21/2021] [Accepted: 09/24/2021] [Indexed: 01/18/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.
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Affiliation(s)
- Thais Oliveira
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74074, USA.
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- Evan Hermann
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74074, USA.
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- Daniel Lin
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74074, USA.
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- Winyoo Chowanadisai
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74074, USA.
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- Elizabeth Hull
- Biomedical Sciences, Midwestern University, Glendale, AZ, 85308, USA.
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- McKale Montgomery
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74074, USA.
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17
Rakowski M, Porębski S, Grzelak A. Silver Nanoparticles Modulate the Epithelial-to-Mesenchymal Transition in Estrogen-Dependent Breast Cancer Cells In Vitro.
Int J Mol Sci 2021;
22:9203. [PMID:
34502112 PMCID:
PMC8431224 DOI:
10.3390/ijms22179203]
[Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/15/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
Silver nanoparticles (AgNPs) are frequently detected in many convenience goods, such as cosmetics, that are applied directly to the skin. AgNPs accumulated in cells can modulate a wide range of molecular pathways, causing direct changes in cells. The aim of this study is to assess the capability of AgNPs to modulate the metastasis of breast cancer cells through the induction of epithelial-to-mesenchymal transition (EMT). The effect of the AgNPs on MCF-7 cells was investigated via the sulforhodamine B method, the wound healing test, generation of reactive oxygen species (ROS), the standard cytofluorimetric method of measuring the cell cycle, and the expression of EMT marker proteins and the MTA3 protein via Western blot. To fulfill the results, calcium flux and HDAC activity were measured. Additionally, mitochondrial membrane potential was measured to assess the direct impact of AgNPs on mitochondria. The results indicated that the MCF-7 cells are resistant to the cytotoxic effect of AgNPs and have higher mobility than the control cells. Treatment with AgNPs induced a generation of ROS; however, it did not affect the cell cycle but modulated the expression of EMT marker proteins and the MTA3 protein. Mitochondrial membrane potential and calcium flux were not altered; however, the AgNPs did modulate the total HDAC activity. The presented data support our hypothesis that AgNPs modulate the metastasis of MCF-7 cells through the EMT pathway. These results suggest that AgNPs, by inducing reactive oxygen species generation, alter the metabolism of breast cancer cells and trigger several pathways related to metastasis.
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Affiliation(s)
- Michał Rakowski
- The Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, 90-237 Lodz, Poland
- Cytometry Laboratory, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
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- Szymon Porębski
- Cytometry Laboratory, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
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- Agnieszka Grzelak
- Cytometry Laboratory, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
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18
Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL.
Pharmaceutics 2021;
13:pharmaceutics13071062. [PMID:
34371753 PMCID:
PMC8309156 DOI:
10.3390/pharmaceutics13071062]
[Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 12/20/2022] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.
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19
Quiroz-Reyes AG, Delgado-Gonzalez P, Islas JF, Gallegos JLD, Martínez Garza JH, Garza-Treviño EN. Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL.
Pharmaceutics 2021;
13:1062. [DOI:
https:/doi.org/10.3390/pharmaceutics13071062]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.
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20
Vaughan HJ, Zamboni CG, Radant NP, Bhardwaj P, Revai Lechtich E, Hassan LF, Shah K, Green JJ. Poly(beta-amino ester) nanoparticles enable tumor-specific TRAIL secretion and a bystander effect to treat liver cancer.
Mol Ther Oncolytics 2021;
21:377-388. [PMID:
34189258 PMCID:
PMC8208964 DOI:
10.1016/j.omto.2021.04.004]
[Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/12/2021] [Indexed: 01/23/2023] Open
Abstract
Despite initial promise, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based approaches to cancer treatment have yet to yield a clinically approved therapy, due to delivery challenges, a lack of potency, and drug resistance. To address these challenges, we have developed poly(beta-amino ester) (PBAE) nanoparticles (NPs), as well as an engineered cDNA sequence encoding a secretable TRAIL (sTRAIL) protein, to enable reprogramming of liver cancer cells to locally secrete TRAIL protein. We show that sTRAIL initiates apoptosis in transfected cells and has a bystander effect to non-transfected cells. To address TRAIL resistance, NP treatment is combined with histone deacetylase inhibitors, resulting in >80% TRAIL-mediated cell death in target cancer cells and significantly slowed xenograft tumor growth. This anti-cancer effect is specific to liver cancer cells, with up to 40-fold higher cell death in HepG2 cancer cells over human hepatocytes. By combining cancer-specific TRAIL NPs with small-molecule-sensitizing drugs, this strategy addresses multiple challenges associated with TRAIL therapy and offers a new potential approach for cancer treatment.
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Affiliation(s)
- Hannah J. Vaughan
- Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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- Camila G. Zamboni
- Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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- Nicholas P. Radant
- Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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- Pranshu Bhardwaj
- Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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- Esther Revai Lechtich
- Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Laboni F. Hassan
- Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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- Khalid Shah
- Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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- Jordan J. Green
- Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Departments of Ophthalmology, Oncology, Neurosurgery, Materials Science & Engineering, and Chemical & Biomolecular Engineering, and the Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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21
Zhang H, Qin G, Zhang C, Yang H, Liu J, Hu H, Wu P, Liu S, Yang L, Chen X, Zhao X, Wang L, Zhang Y. TRAIL promotes epithelial-to-mesenchymal transition by inducing PD-L1 expression in esophageal squamous cell carcinomas.
J Exp Clin Cancer Res 2021;
40:209. [PMID:
34167551 PMCID:
PMC8223376 DOI:
10.1186/s13046-021-01972-0]
[Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 05/05/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND
Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) was initially considered an immunity guard; however, its function remains controversial. Besides immune cells, lung and colon cancer cells have also been reported to express TRAIL, which can promote tumor invasion and metastasis. However, the biological function and underlying mechanism of action of TRAIL in esophageal squamous cell carcinoma (ESCC) remain poorly elucidated.
METHODS
The ESCC cells stemness, migration, and proliferation ability was assessed by sphere formation, Transwell, and CCK8 assay. The stemness- and epithelial-mesenchymal transition (EMT)- related genes expression levels were analyzed by Western blot and RT-qPCR. The signal activation was conducted by Western blot. The xenograft mouse experiments and lung metastasis model were performed to confirm our findings in vitro.
RESULTS
Herein, we found that TRAIL is a negative predictor in patients with ESCC. To further investigate the biological function of TRAIL, we established TRAIL knockdown and overexpression ESCC cell lines and found that TRAIL induced EMT and promoted tumor aggressiveness. Furthermore, we demonstrated that TRAIL- overexpressing cells upregulated PD-L1 expression, which was dependent on the p-ERK/STAT3 signaling pathway. We obtained similar results when using recombinant human TRAIL. Finally, we validated the biological role and mechanism of action of TRAIL in vivo.
CONCLUSIONS
These findings demonstrate that TRAIL promotes ESCC progression by enhancing PD-L1 expression, which induces EMT. This may explain the failure of TRAIL preclinical trials.
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Affiliation(s)
- Huanyu Zhang
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan, 450052, Zhengzhou, China
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- Guohui Qin
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan, 450052, Zhengzhou, China
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- Chaoqi Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
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- Huiyun Yang
- School of Life Sciences, Zhengzhou University, 450052, Zhengzhou, China
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- Jinyan Liu
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
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- Hongwei Hu
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
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- Peng Wu
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
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- Shasha Liu
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
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- Li Yang
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
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- Xinfeng Chen
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan, 450052, Zhengzhou, China
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- Xueke Zhao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan, 450052, Zhengzhou, China
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- Lidong Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan, 450052, Zhengzhou, China
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- Yi Zhang
- Biotherapy Center & Cancer Center, the First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Henan, 450052, Zhengzhou, China.
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan, 450052, Zhengzhou, China.
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Henan Key Laboratory for Tumor Immunology and Biotherapy, 450052, Zhengzhou, China.
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22
Kashio T, Shirakura K, Kinoshita M, Morita M, Ishiba R, Muraoka K, Kanbara T, Tanaka M, Funatsu R, Hino N, Koyama S, Suzuki R, Yoshioka Y, Aoshi T, Doi T, Okada Y. HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells.
Tissue Barriers 2021;
9:1911195. [PMID:
33955828 DOI:
10.1080/21688370.2021.1911195]
[Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Roundabout guidance receptor 4 (Robo4) is an endothelial-specific membrane protein that suppresses pathological angiogenesis and vascular hyperpermeability by stabilizing endothelial cells. Robo4 suppresses severe systemic inflammation induced by pathogens and endotoxins and inhibits tumor growth and metastasis, therefore serving as a potential therapeutic target. Although the regulation of Robo4 expression through transcription factors and epigenetic mechanisms has been studied, the role of histone deacetylases (HDACs) has not been explored. In the present study, we investigated the involvement of HDACs in the regulation of Robo4 expression. An HDAC inhibitor, MS-275, which inhibits HDAC1, HDAC2, and HDAC3, was found to suppress Robo4 expression in endothelial cells. Small interfering RNA (siRNA)-mediated knockdown of HDAC3, but not of HDAC1 and 2, also decreased its expression level. MS-275 downregulated the expression of the transcription factor complex GABP, in addition to suppressing Robo4 promoter activity. GABP expression was also downregulated by the siRNA against HDAC3. MS-275 decreased the transendothelial electrical resistance of a monolayer of mouse endothelial cells and increased the rate of leakage of Evans blue dye in the mouse lungs. In addition, MS-275 accelerated cell migration through the endothelial cell monolayer and augmented cell extravasation in the mouse lungs. Taken together, we demonstrated that MS-275 suppresses Robo4 expression by inhibiting HDAC3 in endothelial cells and enhances endothelial and vascular permeability. Thus, we demonstrated a novel mechanism regulating Robo4 expression and vascular permeability, which is anticipated to contribute to future therapies for infectious and inflammatory diseases.
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Affiliation(s)
- Taito Kashio
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Keisuke Shirakura
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Mayumi Kinoshita
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Maaya Morita
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Ryosuke Ishiba
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Kosuke Muraoka
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Tomoaki Kanbara
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Masato Tanaka
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Risa Funatsu
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Nobumasa Hino
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Shohei Koyama
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
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- Ryo Suzuki
- Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.,Advanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan
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- Yasuo Yoshioka
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,Vaccine Creation Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.,BIKEN Center for Innovative Vaccine Research and Development, the Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan
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- Taiki Aoshi
- Department of Cellular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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- Takefumi Doi
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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- Yoshiaki Okada
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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23
Goh CY, Patmore S, Smolenski A, Howard J, Evans S, O'Sullivan J, McCann A. The role of von Willebrand factor in breast cancer metastasis.
Transl Oncol 2021;
14:101033. [PMID:
33571850 PMCID:
PMC7876567 DOI:
10.1016/j.tranon.2021.101033]
[Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 01/12/2021] [Accepted: 01/28/2021] [Indexed: 01/16/2023] Open
Abstract
VWF plays an important role in breast tumour progression and metastasis.
Patients with metastatic breast cancer have significantly elevated plasma VWF.
Increased levels of highly adhesive VWF may regulate platelet-tumour interactions.
VWF may protect disseminated tumour cells from chemotherapy.
Breast cancer is the most common female cancer globally, with approximately 12% of patients eventually developing metastatic disease. Critically, limited effective treatment options exist for metastatic breast cancer. Recently, von Willebrand factor (VWF), a haemostatic plasma glycoprotein, has been shown to play an important role in tumour progression and metastasis. In breast cancer, a significant rise in the plasma levels of VWF has been reported in patients with malignant disease compared to benign conditions and healthy controls, with an even greater increase seen in patients with disseminated disease. Direct interactions between VWF, tumour cells, platelets and endothelial cells may promote haematogenous dissemination and thus the formation of metastatic foci. Intriguingly, patients with metastatic disease have unusually large VWF multimers. This observation has been proposed to be a result of a dysfunctional or deficiency of VWF-cleaving protease activity, ADAMTS-13 activity, which may then regulate the platelet-tumour adhesive interactions in the metastatic process. In this review, we provide an overview of VWF in orchestrating the pathological process of breast cancer dissemination, and provide supporting evidence of the role of VWF in mediating metastatic breast cancer.
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Affiliation(s)
- Chia Yin Goh
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
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- Sean Patmore
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Dublin 2, Ireland
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- Albert Smolenski
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland
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- Jane Howard
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland
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- Shane Evans
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland
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- Jamie O'Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Dublin 2, Ireland
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- Amanda McCann
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland
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24
Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells.
Cancers (Basel) 2021;
13:cancers13020259. [PMID:
33445642 PMCID:
PMC7827456 DOI:
10.3390/cancers13020259]
[Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/11/2020] [Accepted: 01/08/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary
The triple receptor negative breast cancer subtype, or TNBC, currently has no tailored treatment options. TNBC is highly metastatic, associated with high patient mortality, and disproportionately occurs in Black/African American women where it contributes to racial disparities in health outcomes. Therefore, we focused on new therapeutic approaches to TNBC. We discovered that levels of the Calcium-ATPase SPCA2 are abnormally low in TNBC and that these low levels correlate with poor survival prognosis in patients. Previously, we showed that recombinant SPCA2 prevented TNBC cells from acquiring aggressive “mesenchymal” properties associated with metastasis both in vitro and in vivo. These findings motivated us to search for drugs that turn the SPCA2 gene back on in TNBC cells. In this study, we show that histone deacetylase inhibitors increase SPCA2 levels, activate Ca2+ signaling and convert cancer cells to a less aggressive “epithelial” state. These findings could lead to new treatment options for TNBC.
Abstract
The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.
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25
Wei X, Chen Y, Jiang X, Peng M, Liu Y, Mo Y, Ren D, Hua Y, Yu B, Zhou Y, Liao Q, Wang H, Xiang B, Zhou M, Li X, Li G, Li Y, Xiong W, Zeng Z. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments.
Mol Cancer 2021;
20:7. [PMID:
33397409 PMCID:
PMC7784348 DOI:
10.1186/s12943-020-01288-1]
[Citation(s) in RCA: 260] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
Background
Vasculogenic mimicry (VM) is a recently discovered angiogenetic process found in many malignant tumors, and is different from the traditional angiogenetic process involving vascular endothelium. It involves the formation of microvascular channels composed of tumor cells; therefore, VM is considered a new model for the formation of new blood vessels in aggressive tumors, and can provide blood supply for tumor growth. Many studies have pointed out that in recent years, some clinical treatments against angiogenesis have not been satisfactory possibly due to the activation of VM. Although the mechanisms underlying VM have not been fully elucidated, increasing research on the soil “microenvironment” for tumor growth suggests that the initial hypoxic environment in solid tumors is inseparable from VM.
Main body
In this review, we describe that the stemness and differentiation potential of cancer stem cells are enhanced under hypoxic microenvironments, through hypoxia-induced epithelial-endothelial transition (EET) and extracellular matrix (ECM) remodeling to form the specific mechanism of vasculogenic mimicry; we also summarized some of the current drugs targeting VM through these processes, suggesting a new reference for the clinical treatment of tumor angiogenesis.
Conclusion
Overall, the use of VM inhibitors in combination with conventional anti-angiogenesis treatments is a promising strategy for improving the effectiveness of targeted angiogenesis treatments; further, considering the importance of hypoxia in tumor invasion and metastasis, drugs targeting the hypoxia signaling pathway seem to achieve good results.
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Affiliation(s)
- Xiaoxu Wei
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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- Yunhua Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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- Xianjie Jiang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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- Miao Peng
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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- Yiduo Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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- Yongzhen Mo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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- Daixi Ren
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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- Yuze Hua
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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- Boyao Yu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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- Yujuan Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
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- Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
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- Hui Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
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- Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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- Ming Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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- Xiaoling Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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- Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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- Yong Li
- Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
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- Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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- Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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26
Peyre L, Meyer M, Hofman P, Roux J. TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms.
Br J Cancer 2021;
124:91-101. [PMID:
33257838 PMCID:
PMC7782794 DOI:
10.1038/s41416-020-01177-w]
[Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
The continuing efforts to exploit the death receptor agonists, such as the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), for cancer therapy, have largely been impaired by the anti-apoptotic and pro-survival signalling pathways leading to drug resistance. Cell migration, invasion, differentiation, immune evasion and anoikis resistance are plastic processes sharing features of the epithelial-to-mesenchymal transition (EMT) that have been shown to give cancer cells the ability to escape cell death upon cytotoxic treatments. EMT has recently been suggested to drive a heterogeneous cellular environment that appears favourable for tumour progression. Recent studies have highlighted a link between EMT and cell sensitivity to TRAIL, whereas others have highlighted their effects on the induction of EMT. This review aims to explore the molecular mechanisms by which death signals can elicit an increase in response heterogeneity in the metastasis context, and to evaluate the impact of these processes on cell responses to cancer therapeutics.
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Affiliation(s)
- Ludovic Peyre
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France
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- Mickael Meyer
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France
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- Paul Hofman
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France
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- Jérémie Roux
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France.
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27
Zhang BJ, Chen D, Dekker FJ, Quax WJ. Improving TRAIL-induced apoptosis in cancers by interfering with histone modifications.
CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020;
3:791-803. [PMID:
35582230 PMCID:
PMC8992553 DOI:
10.20517/cdr.2020.58]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/17/2020] [Accepted: 08/19/2020] [Indexed: 11/12/2022]
Abstract
Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription. Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription. In this review, we provide an overview of recent studies on the role of histone modifications in carcinogenesis. Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are well-considered as promising anti-tumour therapies, we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers. In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.
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Affiliation(s)
- Bao-Jie Zhang
- University of Groningen, Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen 9713 AV, The Netherlands
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- Deng Chen
- University of Groningen, Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen 9713 AV, The Netherlands
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- Frank J. Dekker
- University of Groningen, Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen 9713 AV, The Netherlands
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- Wim J. Quax
- University of Groningen, Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen 9713 AV, The Netherlands
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28
Li H, Xu X, Zhang Y, Tang X, Li W. Tetrandrine enhances antitumor effects of the histone deacetylase inhibitor MS-275 in human cancer in a Bax- and p53-dependent manner.
Eur J Pharmacol 2020;
888:173575. [PMID:
32950498 DOI:
10.1016/j.ejphar.2020.173575]
[Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 09/10/2020] [Accepted: 09/14/2020] [Indexed: 10/23/2022]
Abstract
MS-275 (Entinostat), is an oral histone deacetylase (HDAC) inhibitor with a high specificity for class 1 HDACs. As single agent, MS-275 exerts only modest antitumor activity against most solid malignancies. The use of MS-275 in combination with other anticancer agents is currently being evaluated to determine whether this approach can achieve superior therapeutic efficacy. Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the root of a Chinese medicinal herb, is safe and exhibits low toxicity, showing great potential to enhance chemotherapeutic efficacy. In the present study, we investigated the synergistic antitumor effects of MS-275 in combination with tetrandrine. Based on the results of in vitro experiments, the application of MS-275 in combination with tetrandrine induced selective apoptotic death in various cancer cells but spared normal cells. Mechanistically, the combination treatment induced a dramatic accumulation of reactive oxygen species (ROS), and a pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) significantly prevented the cellular apoptosis induced by MS-275/tetrandrine. Moreover, molecular assays indicated that Bax and p53 were the key regulators of MS-275/tetrandrine induced apoptosis. The results of the in vivo studies were consistent with the results of the in vitro studies. Based on our findings, tetrandrine enhanced the antitumor effects of MS-275 in a Bax- and p53-dependent manner. The combination of MS-275 and tetrandrine may represent a novel and promising therapeutic strategy for cancer.
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Affiliation(s)
- Han Li
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, PR China
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- Xiaoqing Xu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, PR China
| |
- Yudi Zhang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, PR China
| |
- Xianying Tang
- College of Life Sciences, South-Central University for Nationalities, Wuhan, 430074, PR China
| |
- Wenhua Li
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, PR China.
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29
Mobasheri T, Rayzan E, Shabani M, Hosseini M, Mahmoodi Chalbatani G, Rezaei N. Neuroblastoma-targeted nanoparticles and novel nanotechnology-based treatment methods.
J Cell Physiol 2020;
236:1751-1775. [PMID:
32735058 DOI:
10.1002/jcp.29979]
[Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 07/11/2020] [Accepted: 07/16/2020] [Indexed: 12/17/2022]
Abstract
Neuroblastoma is a complicated pediatric tumor, originating from the neural crest, which is the most prevalent in adrenal glands, but may rarely be seen in some other tissues as well. Studies are focused on developing new strategies through novel chemo- and immuno-therapeutic drug targets. Different types of oncogenes such as MYCN, tumor suppressor genes such as p53, and some structural genes such as vascular endothelial growth factor are considered as targets for neuroblastoma therapy. The individual expression patterns in NB cells make them appropriate for this purpose. The combined effect of nano-drug delivery systems and specific drug targets will result in lower systemic side effects, prolonged therapeutic effects, and improvements in the pharmacokinetic properties of the drugs. Some of these novel drug delivery systems with a focus on liposomes as carriers are also discussed. In this review, genes and protein products that are beneficial as drug targets in the treatment of neuroblastoma have been discussed.
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Affiliation(s)
- Taranom Mobasheri
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| |
- Elham Rayzan
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| |
- Mahsima Shabani
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Baltimore, Maryland
| |
- Mina Hosseini
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| |
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- Nima Rezaei
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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30
Chen J, Li N, Liu B, Ling J, Yang W, Pang X, Li T. Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways.
Life Sci 2020;
248:117469. [PMID:
32109485 DOI:
10.1016/j.lfs.2020.117469]
[Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 02/08/2020] [Accepted: 02/24/2020] [Indexed: 12/20/2022]
Abstract
AIMS
Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms.
MAIN METHODS
MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects.
KEY FINDINGS
Our results demonstrated that SB939 at 0.5-1 μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models.
SIGNIFICANCE
Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.
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Affiliation(s)
- Jing Chen
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
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- Na Li
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China; Center for neurological diseases, The First People's Hospital of Shizuishan, Shizuishan 753200, China
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- Boxia Liu
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
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- Jun Ling
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
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- Wenjun Yang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Fertility Preservation and Maintenance (Ningxia Medical University), Ministry of Education, Yinchuan 750004, China
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- Xiufeng Pang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
| |
- Tao Li
- Department of Oncology, General Hospital of the Ningxia Medical University, Yinchuan 750004, China.
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31
Histone deacetylases, Mbd3/NuRD, and Tet2 hydroxylase are crucial regulators of epithelial-mesenchymal plasticity and tumor metastasis.
Oncogene 2019;
39:1498-1513. [PMID:
31666683 DOI:
10.1038/s41388-019-1081-2]
[Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 12/21/2022]
Abstract
An epithelial-mesenchymal transition (EMT) represents a basic morphogenetic process of high cell plasticity underlying embryogenesis, wound healing, cancer metastasis and drug resistance. It involves a profound transcriptional and epigenetic reprogramming of cells. A critical role of epigenetic modifiers and their specific chromatin modifications has been demonstrated during EMT. However, it has remained elusive whether epigenetic control differs between the dynamic cell state transitions of reversible EMT and the fixed differentiation status of irreversible EMT. We have employed varying EMT models of murine breast cancer cells to identify the key players establishing epithelial-mesenchymal cell plasticity during reversible and irreversible EMT. We demonstrate that the Mbd3/NuRD complex and the activities of histone deacetylases (HDACs), and Tet2 hydroxylase play a critical role in keeping cancer cells in a highly metastatic mesenchymal state. Combinatorial interference with their functions leads to mesenchymal-epithelial transition (MET) and efficiently represses metastasis formation by invasive murine and human breast cancer cells in vivo.
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32
Goto M, Hirata A, Murakami M, Sakai H. Trimer form of tumor necrosis factor-related apoptosis inducing ligand induces apoptosis in canine cell lines derived from mammary tumors.
J Vet Med Sci 2019;
81:1791-1803. [PMID:
31597817 PMCID:
PMC6943331 DOI:
10.1292/jvms.19-0469]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
We evaluated the cytotoxic effect of isoleucine-zipper tumor necrosis factor-related
apoptosis inducing ligand (izTRAIL) against cell lines, B101592, Cha, and C090115, derived
from canine mammary gland tumors. These cells were derived from three dogs diagnosed with
mammary adenoma or carcinoma. All three cells were positive for vimentin, while B101592
and C090115 were positive for cytokeratin (CK) AE1/AE3 and CK CAM5.2. Treatment with
izTRAIL decreased the viability of the three cell lines. The proportion of annexin
V+/propidium iodide- cells increased in all three cell lines after treatment with izTRAIL.
Additionally, cell cycle analysis revealed that izTRAIL treatment increased the number of
cells in sub-G1 phase. Moreover, izTRAIL treatment activated caspase-8 and caspase-3 and
enhanced the levels of cleaved poly (ADP-ribose) polymerase. The cytotoxic effect of
izTRAIL was mitigated upon co-treatment with caspase-8 or caspase-3 inhibitor. These
results indicated that izTRAIL induces apoptosis in cell lines derived from canine mammary
tumor, which was also previously reported in canine hemangiosarcoma cell lines. This
suggested that canine tumor cells have conserved TRAIL receptors. This study will provide
the basis for further studies on TRAIL receptors and TRAIL-related molecules.
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Affiliation(s)
- Minami Goto
- Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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- Akihiro Hirata
- Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.,Division of Animal Experiment, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
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- Mami Murakami
- Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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- Hiroki Sakai
- Laboratory of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.,Center for Highly Advanced Integration of Nano and Life Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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33
Autin P, Blanquart C, Fradin D. Epigenetic Drugs for Cancer and microRNAs: A Focus on Histone Deacetylase Inhibitors.
Cancers (Basel) 2019;
11:E1530. [PMID:
31658720 PMCID:
PMC6827107 DOI:
10.3390/cancers11101530]
[Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/09/2019] [Accepted: 10/03/2019] [Indexed: 02/06/2023] Open
Abstract
Over recent decades, it has become clear that epigenetic abnormalities are involved in the hallmarks of cancer. Histone modifications, such as acetylation, play a crucial role in cancer development and progression, by regulating gene expression, such as for oncogenes or tumor suppressor genes. Therefore, histone deacetylase inhibitors (HDACi) have recently shown efficacy against both hematological and solid cancers. Designed to target histone deacetylases (HDAC), these drugs can modify the expression pattern of numerous genes including those coding for micro-RNAs (miRNA). miRNAs are small non-coding RNAs that regulate gene expression by targeting messenger RNA. Current research has found that miRNAs from a tumor can be investigated in the tumor itself, as well as in patient body fluids. In this review, we summarized current knowledge about HDAC and HDACi in several cancers, and described their impact on miRNA expression. We discuss briefly how circulating miRNAs may be used as biomarkers of HDACi response and used to investigate response to treatment.
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Affiliation(s)
- Pierre Autin
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
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- Christophe Blanquart
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
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- Delphine Fradin
- CRCINA, INSERM, Université d'Angers, Université de Nantes, 44007 Nantes, France.
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34
Wawruszak A, Gumbarewicz E, Okon E, Jeleniewicz W, Czapinski J, Halasa M, Okla K, Smok-Kalwat J, Bocian A, Rivero-Muller A, Stepulak A. Histone deacetylase inhibitors reinforce the phenotypical markers of breast epithelial or mesenchymal cancer cells but inhibit their migratory properties.
Cancer Manag Res 2019;
11:8345-8358. [PMID:
31571991 PMCID:
PMC6750858 DOI:
10.2147/cmar.s210029]
[Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 09/04/2019] [Indexed: 12/24/2022] Open
Abstract
Introduction
Histone deacetylase inhibitors (HDIs) are a group of compounds that exhibit anticancer activity, but their significance and usefulness in breast cancer (BC) treatment are still controversial. The ability of cancer cells to invade and migrate is augmented by the acquisition of a mesenchymal phenotype – a process known as epithelial-to-mesenchymal transition (EMT). Changes in the expression level of different cadherins, so-called cadherin switches, have been used to monitor the EMT process in development and tumor progression, in particular migration and invasion potential. The aim of this study was to analyze the influence of two HDIs – valproic acid (VPA) and vorinostat (SAHA) – on the migration potential of different BC cell types, as well as on EMT, or its reverse process – mesenchymal-to-epithelial transition, progression by means of shift in epithelial and mesenchymal marker expression.
Methods
HDI treatment-induced expression of E- and N-cadherin at the mRNA and protein levels was evaluated by qPCR, Western blotting and immunostaining methods, respectively. BC cell proliferation and migration were assessed by BrdU, xCELLigence system and wound-healing assay.
Results
VPA and SAHA inhibited the proliferation and migration in a dose- and time-dependent manner, regardless of the BC cell type. Unawares, BC cells having a more mesenchymal phenotype (MDA-MB-468) were found to overexpress N-cadherin, whereas BC lines having an epithelial phenotype (T47D, MCF7) responded to HDI treatment by a significant increase of E-cadherin expression.
Discussion
We suggest that HDAC inhibition results in a more relaxed chromatin concomitant to an increase in the expression of already expressing genes.
Conclusion
By using multiple cancer cell lines, we conclude that HDI induction or reversal of EMT is not a universal mechanism, yet inhibition of cell migration is, and thus EMT should not be considered as the only measurement for tumor aggressiveness.
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Affiliation(s)
- Anna Wawruszak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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- Ewelina Gumbarewicz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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- Estera Okon
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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- Witold Jeleniewicz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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- Jakub Czapinski
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.,School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
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- Marta Halasa
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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- Karolina Okla
- The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Lublin, Poland.,Tumor Immunology Laboratory, Medical University of Lublin, Lublin, Poland
| |
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- Artur Bocian
- Department of Oncological Surgery, Holy Cross Cancer Centre, Kielce, Poland
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- Adolfo Rivero-Muller
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.,Faculty of Science and Engineering, Cell Biology, Abo Akademi University, Turku, Finland
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- Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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35
Blanquart C, Linot C, Cartron PF, Tomaselli D, Mai A, Bertrand P. Epigenetic Metalloenzymes.
Curr Med Chem 2019;
26:2748-2785. [PMID:
29984644 DOI:
10.2174/0929867325666180706105903]
[Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022]
Abstract
Epigenetics controls the expression of genes and is responsible for cellular phenotypes. The fundamental basis of these mechanisms involves in part the post-translational modifications (PTMs) of DNA and proteins, in particular, the nuclear histones. DNA can be methylated or demethylated on cytosine. Histones are marked by several modifications including acetylation and/or methylation, and of particular importance are the covalent modifications of lysine. There exists a balance between addition and removal of these PTMs, leading to three groups of enzymes involved in these processes: the writers adding marks, the erasers removing them, and the readers able to detect these marks and participating in the recruitment of transcription factors. The stimulation or the repression in the expression of genes is thus the result of a subtle equilibrium between all the possibilities coming from the combinations of these PTMs. Indeed, these mechanisms can be deregulated and then participate in the appearance, development and maintenance of various human diseases, including cancers, neurological and metabolic disorders. Some of the key players in epigenetics are metalloenzymes, belonging mostly to the group of erasers: the zinc-dependent histone deacetylases (HDACs), the iron-dependent lysine demethylases of the Jumonji family (JMJ or KDM) and for DNA the iron-dependent ten-eleven-translocation enzymes (TET) responsible for the oxidation of methylcytosine prior to the demethylation of DNA. This review presents these metalloenzymes, their importance in human disease and their inhibitors.
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Affiliation(s)
- Christophe Blanquart
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
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- Camille Linot
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France
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- Pierre-François Cartron
- CRCINA, INSERM, Universite d'Angers, Universite de Nantes, Nantes, France.,Réseau Epigénétique du Cancéropôle Grand Ouest, France
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- Daniela Tomaselli
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy
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- Antonello Mai
- Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.,Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
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- Philippe Bertrand
- Réseau Epigénétique du Cancéropôle Grand Ouest, France.,Institut de Chimie des Milieux et Matériaux de Poitiers, UMR CNRS 7285, 4 rue Michel Brunet, TSA 51106, B27, 86073, Poitiers cedex 09, France
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36
CSCs in Breast Cancer-One Size Does Not Fit All: Therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs.
Cancers (Basel) 2019;
11:cancers11081128. [PMID:
31394796 PMCID:
PMC6721464 DOI:
10.3390/cancers11081128]
[Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/02/2019] [Accepted: 08/04/2019] [Indexed: 02/06/2023] Open
Abstract
Unlike other breast cancer subtypes, triple-negative breast cancer (TNBC) has no specific targets and is characterized as one of the most aggressive subtypes of breast cancer that disproportionately accounts for the majority of breast cancer-related deaths. Current conventional chemotherapeutics target the bulk tumor population, but not the cancer stem cells (CSCs) that are capable of initiating new tumors to cause disease relapse. Recent studies have identified distinct epithelial-like (E) ALDH+ CSCs, mesenchymal-like (M) CD44+/CD24- CSCs, and hybrid E/M ALDH+/CD44+/CD24- CSCs. These subtypes of CSCs exhibit differential signal pathway regulations, possess plasticity, and respond differently to treatment. As such, co-inhibition of different subtypes of CSCs is key to viable therapy. This review serves to highlight different pathway regulations in E and M CSCs in TNBC, and to further describe their role in disease progression. Potential inhibitors targeting E and/or M CSCs based on clinical trials are summarized for further investigation. Since future research needs to adopt suitable tumor models and take into account the divergence of E and M CSCs for the development of effective treatments, TNBC models for clinically translatable studies are further discussed.
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37
Li K, Xu C, Du Y, Junaid M, Kaushik AC, Wei DQ. Comprehensive epigenetic analyses reveal master regulators driving lung metastasis of breast cancer.
J Cell Mol Med 2019;
23:5415-5431. [PMID:
31215771 PMCID:
PMC6653217 DOI:
10.1111/jcmm.14424]
[Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/30/2019] [Accepted: 05/12/2019] [Indexed: 01/02/2023] Open
Abstract
The lung metastasis of breast cancer involves complicated regulatory changes driven by chromatin remodelling. However, the epigenetic reprogramming and regulatory mechanisms in lung metastasis of breast cancer remain unclear. Here, we generated and analysed genome‐wide profiles of multiple histone modifications (H3K4me3, H3K27ac, H3K27me3, H3K4me1 and H3K9me3), as well as transcriptome data in lung‐metastatic and non‐lung‐metastatic breast cancer cells. Our results showed that the expression changes were correlated with the enrichment of specific histone modifications in promoters and enhancers. Promoter and enhancer reprogramming regulated gene expression in a synergetic way, and involved in multiple important biological processes and pathways. In addition, lots of gained super‐enhancers were identified in lung‐metastatic cells. We also identified master regulators driving differential gene expression during lung metastasis of breast cancer. We found that the cooperations between regulators were much closer in lung‐metastatic cells. Moreover, regulators such as TFAP2C, GTF2I and LMO4 were found to have potential prognostic value for lung metastasis free (LMF) survival of breast cancer. Functional studies motivated by our data analyses uncovered an important role of LMO4 in regulating metastasis. This study provided comprehensive insights into regulatory mechanisms, as well as potential prognostic markers for lung metastasis of breast cancer.
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Affiliation(s)
- Kening Li
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University, Shanghai, China
| |
- Congling Xu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University, Shanghai, China
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- Yuxin Du
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University, Shanghai, China
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- Muhammad Junaid
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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- Aman-Chandra Kaushik
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| |
- Dong-Qing Wei
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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38
Wawruszak A, Kalafut J, Okon E, Czapinski J, Halasa M, Przybyszewska A, Miziak P, Okla K, Rivero-Muller A, Stepulak A. Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells.
Cancers (Basel) 2019;
11:cancers11020148. [PMID:
30691229 PMCID:
PMC6406474 DOI:
10.3390/cancers11020148]
[Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 01/18/2019] [Accepted: 01/22/2019] [Indexed: 12/12/2022] Open
Abstract
Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.
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Affiliation(s)
- Anna Wawruszak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
| |
- Joanna Kalafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
| |
- Estera Okon
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
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- Jakub Czapinski
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Trojdena 2a St., 02-091 Warsaw, Poland.
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- Marta Halasa
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
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- Alicja Przybyszewska
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
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- Paulina Miziak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
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- Karolina Okla
- The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland.
- Tumor Immunology Laboratory, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland.
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- Adolfo Rivero-Muller
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
- Faculty of Science and Engineering, Cell Biology, Abo Akademi University, Tykistokatu 6A, 20520 Turku, Finland.
| |
- Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1 St., 20-093 Lublin, Poland.
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39
Wu YS, Lee ZY, Chuah LH, Mai CW, Ngai SC. Epigenetics in Metastatic Breast Cancer: Its Regulation and Implications in Diagnosis, Prognosis and Therapeutics.
Curr Cancer Drug Targets 2019;
19:82-100. [PMID:
29714144 DOI:
10.2174/1568009618666180430130248]
[Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/21/2018] [Accepted: 04/03/2018] [Indexed: 02/06/2023]
Abstract
Despite advances in the treatment regimen, the high incidence rate of breast cancer (BC) deaths is mostly caused by metastasis. Recently, the aberrant epigenetic modifications, which involve DNA methylation, histone modifications and microRNA (miRNA) regulations become attractive targets to treat metastatic breast cancer (MBC). In this review, the epigenetic alterations of DNA methylation, histone modifications and miRNA regulations in regulating MBC are discussed. The preclinical and clinical trials of epigenetic drugs such as the inhibitor of DNA methyltransferase (DNMTi) and the inhibitor of histone deacetylase (HDACi), as a single or combined regimen with other epigenetic drug or standard chemotherapy drug to treat MBCs are discussed. The combined regimen of epigenetic drugs or with standard chemotherapy drugs enhance the therapeutic effect against MBC. Evidences that epigenetic changes could have implications in diagnosis, prognosis and therapeutics for MBC are also presented. Several genes have been identified as potential epigenetic biomarkers for diagnosis and prognosis, as well as therapeutic targets for MBC. Endeavors in clinical trials of epigenetic drugs against MBC should be continued although limited success has been achieved. Future discovery of epigenetic drugs from natural resources would be an attractive natural treatment regimen for MBC. Further research is warranted in translating research into clinical practice with the ultimate goal of treating MBC by epigenetic therapy in the near future.
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Affiliation(s)
- Yuan Seng Wu
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, Selangor, Malaysia
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
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- Zhong Yang Lee
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, Selangor, Malaysia
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- Lay-Hong Chuah
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
- Advanced Engineering Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
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- Chun Wai Mai
- Department of Pharmaceutical Chemistry, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
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- Siew Ching Ngai
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, Selangor, Malaysia
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40
Su Y, Hopfinger NR, Nguyen TD, Pogash TJ, Santucci-Pereira J, Russo J. Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018;
37:314. [PMID:
30547810 PMCID:
PMC6295063 DOI:
10.1186/s13046-018-0988-8]
[Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 11/30/2018] [Indexed: 12/23/2022]
Abstract
Background
Triple negative breast cancer (TNBC) is an aggressive neoplasia with no effective therapy. Our laboratory has developed a unique TNBC cell model presenting epithelial mesenchymal transition (EMT) a process known to be important for tumor progression and metastasis. There is increasing evidence showing that epigenetic mechanisms are involved in the activation of EMT. The objective of this study is to epigenetically reverse the process of EMT in TNBC by using DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi).
Methods
We evaluated the antitumor effect of three DNMTi and six HDACi using our TNBC cell model by MTT assay, migration and invasion assay, three dimensional culture, and colony formation assay. We then performed the combined treatment both in vitro and in vivo using the most potent DNMTi and HDACi, and tested the combined treatment in a panel of breast cancer cell lines. We investigated changes of EMT markers and potential signaling pathways associated with the antitumor effects.
Results
We showed that DNMTi and HDACi can reprogram highly aggressive TNBC cells that have undergone EMT to a less aggressive phenotype. SGI-110 and MS275 are superior to other seven compounds being tested. The combination of SGI with MS275 exerts a greater effect than single agent alone in inhibiting cell proliferation, motility, colony formation, and stemness of cancer cells. We also demonstrated that MS275 and the combination of SGI with MS275 exert in vivo antitumor effect. We revealed that the combined treatment synergistically reverses EMT through inhibiting EpCAM cleavage and WNT signaling, suppressing mutant p53, ZEB1, and EZH2, and inducing E-cadherin, apoptosis, as well as histone H3 tri-methylation.
Conclusions
Our study showed that DNMTi and HDACi exert antitumor activity in TNBC cells partially by epigenetically reprograming EMT. Our findings strongly suggest that TNBC is sensitive to epigenetic therapies. Therefore, we propose a new strategy to treat TNBC by using the combination of SGI-110 with MS275, which exerts superior antitumor effects by simultaneously targeting multiple pathways.
Electronic supplementary material
The online version of this article (10.1186/s13046-018-0988-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yanrong Su
- The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA, 19111, USA.
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- Nathan R Hopfinger
- The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA, 19111, USA
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- Theresa D Nguyen
- The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA, 19111, USA
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- Thomas J Pogash
- The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA, 19111, USA
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- Julia Santucci-Pereira
- The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA, 19111, USA
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- Jose Russo
- The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA, 19111, USA.
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41
Gurunathan S, Kang MH, Kim JH. Combination Effect of Silver Nanoparticles and Histone Deacetylases Inhibitor in Human Alveolar Basal Epithelial Cells.
Molecules 2018;
23:molecules23082046. [PMID:
30111752 PMCID:
PMC6222610 DOI:
10.3390/molecules23082046]
[Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 08/09/2018] [Accepted: 08/10/2018] [Indexed: 01/15/2023] Open
Abstract
Although many treatment strategies have been reported for lung disease, the mechanism of combination therapy using silver nanoparticles (AgNPs) and histone deacetylases inhibitors (HDACi) remains unclear. Therefore, innovative treatment strategies are essential for addressing the therapeutic challenges of this highly aggressive lung cancer. AgNPs and HDACi seem to be the best candidates for anticancer therapy because of their anti-proliferative effect in a variety of cancer cells. First, we synthesized AgNPs using wogonin as a reducing and stabilizing agent, following which the synthesized AgNPs were characterized by various analytical techniques. The synthesized AgNPs exhibited dose- and size-dependent toxicity towards A549 cells. Interestingly, the combination of AgNPs and MS-275 significantly induces apoptosis, which was accompanied by an increased level of reactive oxygen species (ROS); leakage of lactate dehydrogenase (LDH); secretion of TNFα; dysfunction of mitochondria; accumulation autophagosomes; caspase 9/3 activation; up and down regulation of pro-apoptotic genes and anti-apoptotic genes, respectively; and eventually, induced DNA-fragmentation. Our findings suggest that AgNPs and MS-275 induce cell death in A549 lung cells via the mitochondrial-mediated intrinsic apoptotic pathway. Finally, our data show that the combination of AgNPs and MS-275 is a promising new approach for the treatment of lung cancer and our findings contribute to understanding the potential roles of AgNPs and MS-275 in pulmonary disease. However, further study is warranted to potentiate the use of this combination therapy in cancer therapy trials.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
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- Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
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- Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
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42
Rinaldi L, Folliero V, Palomba L, Zannella C, Isticato R, Di Francia R, Berretta M, de Sio I, Adinolfi LE, Morelli G, Lastoria S, Altucci L, Pedone C, Galdiero M, Franci G. Sonoporation by microbubbles as gene therapy approach against liver cancer.
Oncotarget 2018;
9:32182-32190. [PMID:
30181808 PMCID:
PMC6114955 DOI:
10.18632/oncotarget.25875]
[Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 07/13/2018] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION
An innovative method, known as sonoporation, was used to induce the expression of silenced genes, such as (but not restricted to) TRAIL and p53, in liver cancer cells (HepG2). The principal aim of the present study was the re-activation of silenced apoptotic pathways in liver cancer models, by using diagnostic synovial microbubble as plasmid gene delivery tools in combination with epigenetic treatments.
MATERIAL AND METHODS
HepG2 cells were used as a liver cancer model. Microbubbles (Sonovue®) were chosen as gene deliver system in combination with the sonoporation approach. Plasmid pEGFP-TRAIL and pEGFP-p53 were selected and propagated in Escherichia coli grown in LB broth, in order to obtain the necessary amount.
RESULTS
Sonoporation was induced by using transducer (Sonitron 2000) and, among the several conditions tested, 3 MHz, 51% Duty Cycle, and 5 W/cm2, 30 s resulted as the best parameters. Data collected showed a dose dependent effect in terms of output energy. A transfection efficacy of 30 - 50% was achieved and recombinant gene expression induced apoptotic effects. In order to increase efficacy, we used the histone deacetylase inhibitor (HDACi, entinostat) MS-275, able to activate TRAIL and thus inducing a stronger pro-apoptotic effect in combination with TRAIL-gene re-expression.
CONCLUSION
For the first time, it was shown the possibility to induce the exogenous expression of the pro-apoptotic gene TRAIL and p53 in a liver cancer HepG2 cells via a sonoporation procedure. The epigenetic treatment using HDACi was able to increase the pro-apoptotic effects of the gene therapy.
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Affiliation(s)
- Luca Rinaldi
- Department of Medical, Surgical, Neurological, Metabolic and Aging Science, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Veronica Folliero
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Luciana Palomba
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Carla Zannella
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Raffaele Di Francia
- Department of Hematology, National Cancer Institute, Foundation G. Pascale IRCCS, Naples, Italy
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- Ilario de Sio
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Luigi E. Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic and Aging Science, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Secondo Lastoria
- Department of Diagnostic Imaging, Radiation and Metabolic Therapy, National Cancer Institute, Foundation G. Pascale IRCCS, Naples, Italy
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- Lucia Altucci
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Carlo Pedone
- Department of Pharmacology, Federico II University, Naples, Italy
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- Massimiliano Galdiero
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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- Gianluigi Franci
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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43
Kiweler N, Brill B, Wirth M, Breuksch I, Laguna T, Dietrich C, Strand S, Schneider G, Groner B, Butter F, Heinzel T, Brenner W, Krämer OH. The histone deacetylases HDAC1 and HDAC2 are required for the growth and survival of renal carcinoma cells.
Arch Toxicol 2018;
92:2227-2243. [DOI:
10.1007/s00204-018-2229-5]
[Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 05/23/2018] [Indexed: 12/11/2022]
44
Antitumor effects of histone deacetylase inhibitor suberoylanilide hydroxamic acid in epidermal growth factor receptor-mutant non-small-cell lung cancer lines in vitro and in vivo.
Anticancer Drugs 2018;
29:262-270. [PMID:
29356692 DOI:
10.1097/cad.0000000000000597]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Histone acetylation is one of the most abundant post-translational modifications in eukaryotic cells; aberrant histone acetylation is related to a range of cancer types because of the dysregulation of histone deacetylases (HDACs). Inhibition of HDACs leads to suppression of tumor growth in multiple cancers, whereas the inhibitory effects of HDAC inhibitors remain incompletely understood in epidermal growth factor receptor (EGFR)-mutant lung cancers. In this study, the antitumor effects of HDACs inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) were examined in EGFR-mutant lung cancer cell lines. The results of the present work showed that SAHA markedly inhibited cell viability and proliferation, induced cell apoptosis by arresting the cell cycle in the G2/M phase, and significantly reduced tumor growth in a xenograft model. Further study confirmed that the suppression function of SAHA might be mediated by regulating the ERK-dependent and/or the AKT-dependent pathway; meanwhile, angiogenesis abrogation induced by SAHA exerted effects on tumor regression in vivo. Taken together, our results identify the antitumor effects of HDACs inhibitor SAHA as an alternative therapeutic application for the epigenetic treatment of EGFR-mutant non-small-cell lung cancer.
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45
Yeruva SLH, Zhao F, Miller KD, Tevaarwerk AJ, Wagner LI, Gray RJ, Sparano JA, Connolly RM. E2112: randomized phase iii trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer.
NPJ Breast Cancer 2018;
4:1. [PMID:
29354686 PMCID:
PMC5765007 DOI:
10.1038/s41523-017-0053-3]
[Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 12/01/2017] [Accepted: 12/12/2017] [Indexed: 01/29/2023] Open
Abstract
Endocrine therapies are effective in the treatment of hormone receptor (HR)-positive breast cancer, however, de novo or acquired treatment resistance is a significant clinical problem. A potential mechanism of resistance involves changes in gene expression secondary to epigenetic modifications, which might be reversed with the use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 phase II randomized, placebo-controlled study demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS), with the addition of entinostat to exemestane in patients with HR-positive advanced breast cancer with disease progression after prior non-steroidal aromatase inhibitor (AI). These results prompted the development of E2112, a phase III registration trial which is investigating entinostat/placebo in combination with exemestane in patients with locally advanced or metastatic breast cancer who have experienced disease progression after a non-steroidal AI. E2112 aims to validate the preclinical and clinical findings supporting the role of HDAC inhibitors in overcoming resistance to endocrine therapy in breast cancer, and ultimately improve outcomes for patients with advanced breast cancer.
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Affiliation(s)
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- Lynne I. Wagner
- Wake Forest University Health Services, Winston-Salem, NC USA
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- Joseph A. Sparano
- Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
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46
Zhao H, Li D, Zhang B, Qi Y, Diao Y, Zhen Y, Shu X. PP2A as the Main Node of Therapeutic Strategies and Resistance Reversal in Triple-Negative Breast Cancer.
Molecules 2017;
22:molecules22122277. [PMID:
29261144 PMCID:
PMC6149800 DOI:
10.3390/molecules22122277]
[Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 12/07/2017] [Accepted: 12/19/2017] [Indexed: 12/31/2022] Open
Abstract
Triple negative breast cancer (TNBC), is defined as a type of tumor lacking the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The ER, PR and HER2 are usually the molecular therapeutic targets for breast cancers, but they are ineffective for TNBC because of their negative expressions, so chemotherapy is currently the main treatment strategy in TNBC. However, drug resistance remains a major impediment to TNBC chemotherapeutic treatment. Recently, the protein phosphatase 2A (PP2A) has been found to regulate the phosphorylation of some substrates involved in the relevant target of TNBC, such as cell cycle control, DNA damage responses, epidermal growth factor receptor, immune modulation and cell death resistance, which may be the effective therapeutic strategies or influence drug sensitivity to TNBCs. Furthermore, PP2A has also been found that could induce ER re-expression in ER-negative breast cancer cells, and which suggests PP2A could promote the sensitivity of tamoxifen to TNBCs as a resistance reversal agent. In this review, we will summarize the potential therapeutic value of PP2A as the main node in developing targeting agents, disrupting resistance or restoring drug sensitivity in TNBC.
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Affiliation(s)
- Henan Zhao
- Department of Pathophysiology, Dalian Medical University, Dalian 116044, China.
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- Duojiao Li
- Kamp Pharmaceutical Co. Ltd., Changsha 410008, China.
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- Baojing Zhang
- College of Pharmacy, Dalian Medical University, Dalian 116044, China.
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- Yan Qi
- College of Pharmacy, Dalian Medical University, Dalian 116044, China.
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- Yunpeng Diao
- College of Pharmacy, Dalian Medical University, Dalian 116044, China.
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- Yuhong Zhen
- College of Pharmacy, Dalian Medical University, Dalian 116044, China.
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- Xiaohong Shu
- College of Pharmacy, Dalian Medical University, Dalian 116044, China.
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47
Berthier S, Arnaud J, Champelovier P, Col E, Garrel C, Cottet C, Boutonnat J, Laporte F, Faure P, Hazane-Puch F. Anticancer properties of sodium selenite in human glioblastoma cell cluster spheroids.
J Trace Elem Med Biol 2017;
44:161-176. [PMID:
28965572 DOI:
10.1016/j.jtemb.2017.04.012]
[Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 04/24/2017] [Indexed: 01/08/2023]
Abstract
Glioblastoma (GBM) is the most common type of primary tumor of the central nervous system with a poor prognosis, needing the development of new therapeutic drugs. Few studies focused on sodium selenite (SS) effects in cancer cells cultured as multicellular tumor spheroids (MCTS or 3D) closer to in vivo tumor. We investigated SS anticancer effects in three human GBM cell lines cultured in 3D: LN229, U87 (O(6)-methyguanine-DNA-methyltransferase (MGMT) negative) and T98G (MGMT positive). SS absorption was evaluated and the cytotoxicity of SS and temozolomide (TMZ), the standard drug used against GBM, were compared. SS impacts on proliferation, cell death, and invasiveness were evaluated as well as epigenetic modifications by focusing on histone deacetylase (HDAC) activity and dimethyl-histone-3-lysine-9 methylation (H3K9m2), after 24h to 72h SS exposition. SS was absorbed by spheroids and was more cytotoxic than TMZ (i.e., for LN229, the IC50 was 38 fold-more elevated for TMZ than SS, at 72h). SS induced a cell cycle arrest in the S phase and apoptosis via caspase-3. SS decreased carbonic anhydrase-9 (CA9) expression, invasion on a Matrigel matrix and modulated E- and N-Cadherin transcript expressions. SS decreased HDAC activity and modulated H3K9m2 levels. 3D model provides a relevant strategy to screen new drugs and SS is a promising drug against GBM that should now be tested in GBM animal models.
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Affiliation(s)
- Sylvie Berthier
- Cytology Unit, Department of Anatomy and Pathologic Cytology (DACP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France
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- Josiane Arnaud
- Hormonal and Nutritional Biochemistry Unit, Department of Biochemistry, Toxicology and Pharmacology (DBTP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France; University Grenoble Alpes, LBFA and BEeSy, Grenoble, France; Inserm, U1055, Grenoble, France
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- Pierre Champelovier
- Cytology Unit, Department of Anatomy and Pathologic Cytology (DACP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France
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- Edwige Col
- Cytology Unit, Department of Anatomy and Pathologic Cytology (DACP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France
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- Catherine Garrel
- Hormonal and Nutritional Biochemistry Unit, Department of Biochemistry, Toxicology and Pharmacology (DBTP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France
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- Cécile Cottet
- University Grenoble Alpes, LBFA and BEeSy, Grenoble, France; Inserm, U1055, Grenoble, France
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- Jean Boutonnat
- Cytology Unit, Department of Anatomy and Pathologic Cytology (DACP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France
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- François Laporte
- Hormonal and Nutritional Biochemistry Unit, Department of Biochemistry, Toxicology and Pharmacology (DBTP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France
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- Patrice Faure
- Hormonal and Nutritional Biochemistry Unit, Department of Biochemistry, Toxicology and Pharmacology (DBTP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France; Laboratory Hypoxia and Pathology (HP2), Inserm U1042, Faculty of Medicine and Pharmacy, Domaine de la Merci, 38700 La Tronche, France
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- Florence Hazane-Puch
- Hormonal and Nutritional Biochemistry Unit, Department of Biochemistry, Toxicology and Pharmacology (DBTP), Institute of Biology and Pathology, Grenoble Alpes Hospital, CS10217, France.
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48
Wu X, Wang S, Li M, Wang A, Zhou Y, Li P, Wang Y. Nanocarriers for TRAIL delivery: driving TRAIL back on track for cancer therapy.
NANOSCALE 2017;
9:13879-13904. [PMID:
28914952 DOI:
10.1039/c7nr04959e]
[Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Since its initial identification, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to be capable of selectively inducing apoptosis in cancer cells. However, translation of the encouraging preclinical studies of this cytokine into the clinic has been restricted by its extremely short half-life, the presence of resistant cancer cell populations, and its inefficient in vivo delivery. Recently, there has been exceptional progress in developing novel formulations to increase the circulatory half-life of TRAIL and new combinations to treat cancers that are resistant to TRAIL. In particular, TRAIL-based nanotherapies offer the potential to improve the stability of TRAIL and prolong its half-life in plasma, to specifically deliver TRAIL to a particular target site, and to overcome resistance to TRAIL. The aim of this review is to provide an overview of the state-of-the art drug delivery systems that are currently being tested or developed to improve the biological attributes of TRAIL-based therapies.
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Affiliation(s)
- Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan Province, China
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49
Bayat Mokhtari R, Baluch N, Homayouni TS, Morgatskaya E, Kumar S, Kazemi P, Yeger H. The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review.
J Cell Commun Signal 2017;
12:91-101. [PMID:
28735362 DOI:
10.1007/s12079-017-0401-y]
[Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 07/06/2017] [Indexed: 01/25/2023] Open
Abstract
Cancer is a multi-stage process resulting from aberrant signaling pathways driving uncontrolled proliferation of transformed cells. The development and progression of cancer from a premalignant lesion towards a metastatic tumor requires accumulation of mutations in many regulatory genes of the cell. Different chemopreventative approaches have been sought to interfere with initiation and control malignant progression. Here we present research on dietary compounds with evidence of cancer prevention activity that highlights the potential beneficial effect of a diet rich in cruciferous vegetables. The Brassica family of cruciferous vegetables such as broccoli is a rich source of glucosinolates, which are metabolized to isothiocyanate compounds. Amongst a number of related variants of isothiocyanates, sulforaphane (SFN) has surfaced as a particularly potent chemopreventive agent based on its ability to target multiple mechanisms within the cell to control carcinogenesis. Anti-inflammatory, pro-apoptotic and modulation of histones are some of the more important and known mechanisms by which SFN exerts chemoprevention. The effect of SFN on cancer stem cells is another area of interest that has been explored in recent years and may contribute to its chemopreventive properties. In this paper, we briefly review structure, pharmacology and preclinical studies highlighting chemopreventive effects of SFN.
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Affiliation(s)
- Reza Bayat Mokhtari
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada. .,Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. .,Institute of Medical Science, University of Toronto, Toronto, ON, Canada. .,Sickkids Research Center, Peter Gilgan Centre, 686 Bay St., Rm 15.9714, Toronto, ON, M5G 0A4, Canada.
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- Narges Baluch
- Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University, 88 Stuart Street, Kingston, ON, K7L 3N6, Canada
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- Tina S Homayouni
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
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- Evgeniya Morgatskaya
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
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- Sushil Kumar
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
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- Parandis Kazemi
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
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- Herman Yeger
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada. .,Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. .,Institute of Medical Science, University of Toronto, Toronto, ON, Canada. .,Sickkids Research Center, Peter Gilgan Centre, 686 Bay St., Rm 15.9714, Toronto, ON, M5G 0A4, Canada.
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50
Rellinger EJ, Padmanabhan C, Qiao J, Appert A, Waterson AG, Lindsley CW, Beauchamp RD, Chung DH. ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.
Biochem Biophys Res Commun 2017;
491:463-468. [PMID:
28716733 DOI:
10.1016/j.bbrc.2017.07.050]
[Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 07/08/2017] [Indexed: 01/06/2023]
Abstract
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG0 cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
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Affiliation(s)
- Eric J Rellinger
- Section of Surgical Sciences, Department of Surgery, United States; Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
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- Jingbo Qiao
- Section of Surgical Sciences, Department of Surgery, United States; Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
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- Andrew Appert
- Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
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- Alex G Waterson
- Department of Pharmacology, Vanderbilt Institute of Chemical Biology, United States
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- Craig W Lindsley
- Department of Pharmacology, Vanderbilt Institute of Chemical Biology, United States
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- R Daniel Beauchamp
- Section of Surgical Sciences, Department of Surgery, United States; Department of Cancer Biology, United States; Department of Cell and Developmental Biology, United States
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- Dai H Chung
- Section of Surgical Sciences, Department of Surgery, United States; Department of Cancer Biology, United States; Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
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