|
1
|
Chen L, Li X, Wu Y, Wang J, Pi J. Differential analysis of ovarian tissue between high and low-yielded laying hens in the late laying stage and the effect of LECT2 gene on follicular granulosa cells proliferation. Mol Biol Rep 2024; 51:240. [PMID: 38300380 DOI: 10.1007/s11033-024-09260-8] [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: 09/15/2023] [Accepted: 01/15/2024] [Indexed: 02/02/2024]
Abstract
The ovaries of high-yield laying hens exhibited signs of aging beyond 400 days of age, subsequently resulting in a decline in both egg production and egg quality. Oxidative stress, characterized by an increase in the production of reactive oxygen species (ROS), stands as one of the principal processes contributing to ovarian aging. Elevated ROS levels are implicated in the induction of apoptosis in granulosa cells (GCs), provoking mitochondrial impairment, and diminishing the capacity of the antioxidant defense system. This investigation stratified laying hens into two distinct groups, predicated upon their egg production levels: high-yield hens (HH) and low-yield hens (LL). The study focused on evaluating oxidative stress markers and identifying differentially expressed genes between these two groups. The findings revealed that the LL group exhibited follicular atresia, mitochondrial disruptions, and apoptotic occurrences in ovarian GCs. Notably, ROS levels, Malondialdehyde (MDA) concentrations, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations in ovarian tissue and follicular GCs were substantially higher in the HH group. Furthermore, the RNA-sequencing results unveiled differential expression of the LECT2 gene between the HH and LL groups. Consequently, an overexpression vector for the LECT2 gene was successfully constructed and introduced into GCs. The quantitative polymerase chain reaction (QPCR) analysis exhibited significant downregulation (p < 0.01) of key apoptotic genes such as Caspase-3 and C-myc and significant upregulation (p < 0.01) of BCL2 following the overexpression of the LECT2 gene in GCs. In conclusion, oxidative stress emerges as a pivotal factor influencing the laying traits of both high and low-yield laying hens. The accumulation of reactive oxygen species (ROS) within the ovaries precipitates apoptosis in GCs, subsequently leading to follicular atresia and a reduction in egg production. Furthermore, we employed RNA sequencing technology to examine the ovarian matrix tissue in high and low laying hens during the late phase of egg laying. Our analysis revealed a substantial upregulation of the LECT2 gene in the ovarian matrix tissue of high laying hens. This observation implies that the LECT2 gene exerts a pivotal influence on driving the proliferation and differentiation of follicular GCs, thereby exerting a crucial regulatory role in follicular development.
Collapse
Affiliation(s)
- Lin Chen
- Animal Husbandry and Veterinary Research Institute, Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Hubei Academy of Agricultural Sciences, Wuhan, 430000, China
- College of Animal Science, Yangtze University, Jingzhou, 434000, China
| | - Xianqiang Li
- Animal Husbandry and Veterinary Research Institute, Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Hubei Academy of Agricultural Sciences, Wuhan, 430000, China
- College of Animal Science, Yangtze University, Jingzhou, 434000, China
| | - Yan Wu
- Animal Husbandry and Veterinary Research Institute, Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Hubei Academy of Agricultural Sciences, Wuhan, 430000, China.
| | - Jiaxiang Wang
- College of Animal Science, Yangtze University, Jingzhou, 434000, China
| | - Jinsong Pi
- Animal Husbandry and Veterinary Research Institute, Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Hubei Academy of Agricultural Sciences, Wuhan, 430000, China
| |
Collapse
|
|
2
|
Hein T, Krammer PH, Weyd H. Molecular analysis of Annexin expression in cancer. BMC Cancer 2022; 22:994. [PMID: 36123610 PMCID: PMC9484247 DOI: 10.1186/s12885-022-10075-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Background Uptake of apoptotic cells induces a tolerogenic phenotype in phagocytes and promotes peripheral tolerance. The highly conserved Annexin core domain, present in all members of the Annexin family, becomes exposed on the apoptotic cell-surface and triggers tolerogenic signalling in phagocytes via the Dectin-1 receptor. Consequently, Annexins exposed on tumour cells upon cell death are expected to induce tolerance towards tumour antigens, inhibiting tumour rejection. Methods Expression analysis for all Annexin family members was conducted in cancer cell lines of diverse origins. Presentation of Annexins on the cell surface during apoptosis of cancer cell lines was investigated using surface washes and immunoblotting. Expression data from the GEO database was analysed to compare Annexin levels between malignant and healthy tissue. Results Six Annexins at least were consistently detected on mRNA and protein level for each investigated cell line. AnxA1, AnxA2 and AnxA5 constituted the major part of total Annexin expression. All expressed Annexins translocated to the cell surface upon apoptosis induction in all cell lines. Human expression data indicate a correlation between immune infiltration and overall Annexin expression in malignant compared to healthy tissue. Conclusions This study is the first comprehensive analysis of expression, distribution and presentation of Annexins in cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10075-8.
Collapse
Affiliation(s)
- Tobias Hein
- Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Centre, 69120, Heidelberg, Germany.,Faculty of Biosciences, Ruprecht-Karls-University Heidelberg, 69120, Heidelberg, Germany
| | - Peter H Krammer
- Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Centre, 69120, Heidelberg, Germany
| | - Heiko Weyd
- Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Centre, 69120, Heidelberg, Germany.
| |
Collapse
|
|
3
|
Harrington CT, Sotillo E, Dang CV, Thomas-Tikhonenko A. Tilting MYC toward cancer cell death. Trends Cancer 2021; 7:982-994. [PMID: 34481764 PMCID: PMC8541926 DOI: 10.1016/j.trecan.2021.08.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022]
Abstract
MYC oncoprotein promotes cell proliferation and serves as the key driver in many human cancers; therefore, considerable effort has been expended to develop reliable pharmacological methods to suppress its expression or function. Despite impressive progress, MYC-targeting drugs have not reached the clinic. Recent advances suggest that within a limited expression range unique to each tumor, MYC oncoprotein can have a paradoxical, proapoptotic function. Here we introduce a counterintuitive idea that modestly and transiently elevating MYC levels could aid chemotherapy-induced apoptosis and thus benefit the patients as much, if not more than MYC inhibition.
Collapse
Affiliation(s)
- Colleen T Harrington
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Elena Sotillo
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Chi V Dang
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA; Ludwig Institute for Cancer Research, New York, NY 10017, USA
| | - Andrei Thomas-Tikhonenko
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
4
|
Carroll PA, Freie BW, Cheng PF, Kasinathan S, Gu H, Hedrich T, Dowdle JA, Venkataramani V, Ramani V, Wu X, Raftery D, Shendure J, Ayer DE, Muller CH, Eisenman RN. The glucose-sensing transcription factor MLX balances metabolism and stress to suppress apoptosis and maintain spermatogenesis. PLoS Biol 2021; 19:e3001085. [PMID: 34669700 PMCID: PMC8528285 DOI: 10.1371/journal.pbio.3001085] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 09/24/2021] [Indexed: 01/02/2023] Open
Abstract
Male germ cell (GC) production is a metabolically driven and apoptosis-prone process. Here, we show that the glucose-sensing transcription factor (TF) MAX-Like protein X (MLX) and its binding partner MondoA are both required for male fertility in the mouse, as well as survival of human tumor cells derived from the male germ line. Loss of Mlx results in altered metabolism as well as activation of multiple stress pathways and GC apoptosis in the testes. This is concomitant with dysregulation of the expression of male-specific GC transcripts and proteins. Our genomic and functional analyses identify loci directly bound by MLX involved in these processes, including metabolic targets, obligate components of male-specific GC development, and apoptotic effectors. These in vivo and in vitro studies implicate MLX and other members of the proximal MYC network, such as MNT, in regulation of metabolism and differentiation, as well as in suppression of intrinsic and extrinsic death signaling pathways in both spermatogenesis and male germ cell tumors (MGCTs).
Collapse
Affiliation(s)
- Patrick A. Carroll
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Brian W. Freie
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Pei Feng Cheng
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Sivakanthan Kasinathan
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Haiwei Gu
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America
| | - Theresa Hedrich
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - James A. Dowdle
- Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Vivek Venkataramani
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Vijay Ramani
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Xiaoying Wu
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Daniel Raftery
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America
| | - Jay Shendure
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
- Howard Hughes Medical Institute, Seattle, Washington, United States of America
- Brotman Baty Institute for Precision Medicine, Seattle, Washington, United States of America
| | - Donald E. Ayer
- Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, United States of America
| | - Charles H. Muller
- Male Fertility Lab, Department of Urology, University of Washington, Seattle, Washington, United States of America
| | - Robert N. Eisenman
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| |
Collapse
|
|
5
|
Trejo-Solis C, Escamilla-Ramirez A, Jimenez-Farfan D, Castillo-Rodriguez RA, Flores-Najera A, Cruz-Salgado A. Crosstalk of the Wnt/β-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells. Pharmaceuticals (Basel) 2021; 14:ph14090871. [PMID: 34577571 PMCID: PMC8465904 DOI: 10.3390/ph14090871] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
The Wnt/β-catenin signaling pathway plays a major role in cell survival and proliferation, as well as in angiogenesis, migration, invasion, metastasis, and stem cell renewal in various cancer types. However, the modulation (either up- or downregulation) of this pathway can inhibit cell proliferation and apoptosis both through β-catenin-dependent and independent mechanisms, and by crosstalk with other signaling pathways in a wide range of malignant tumors. Existing studies have reported conflicting results, indicating that the Wnt signaling can have both oncogenic and tumor-suppressing roles, depending on the cellular context. This review summarizes the available information on the role of the Wnt/β-catenin pathway and its crosstalk with other signaling pathways in apoptosis induction in cancer cells and presents a modified dual-signal model for the function of β-catenin. Understanding the proapoptotic mechanisms induced by the Wnt/β-catenin pathway could open new therapeutic opportunities.
Collapse
Affiliation(s)
- Cristina Trejo-Solis
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
- Correspondence:
| | - Angel Escamilla-Ramirez
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
| | - Dolores Jimenez-Farfan
- Laboratorio de Inmunología, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico;
| | | | - Athenea Flores-Najera
- Centro Médico Nacional 20 de Noviembre, Departamento de Cirugía General, Ciudad de Mexico 03229, Mexico;
| | - Arturo Cruz-Salgado
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
| |
Collapse
|
|
6
|
Ahmadi SE, Rahimi S, Zarandi B, Chegeni R, Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. J Hematol Oncol 2021; 14:121. [PMID: 34372899 PMCID: PMC8351444 DOI: 10.1186/s13045-021-01111-4] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/12/2021] [Indexed: 12/17/2022] Open
Abstract
MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.
Collapse
Affiliation(s)
- Seyed Esmaeil Ahmadi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Rahimi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahman Zarandi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rouzbeh Chegeni
- Medical Laboratory Sciences Program, College of Health and Human Sciences, Northern Illinois University, DeKalb, IL, USA.
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
7
|
Taguchi T, Kodera Y, Oba K, Saito T, Nakagawa Y, Kawashima Y, Shichiri M. Suprabasin-derived bioactive peptides identified by plasma peptidomics. Sci Rep 2021; 11:1047. [PMID: 33441610 PMCID: PMC7806982 DOI: 10.1038/s41598-020-79353-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/08/2020] [Indexed: 01/29/2023] Open
Abstract
Identification of low-abundance, low-molecular-weight native peptides using non-tryptic plasma has long remained an unmet challenge, leaving potential bioactive/biomarker peptides undiscovered. We have succeeded in efficiently removing high-abundance plasma proteins to enrich and comprehensively identify low-molecular-weight native peptides using mass spectrometry. Native peptide sequences were chemically synthesized and subsequent functional analyses resulted in the discovery of three novel bioactive polypeptides derived from an epidermal differentiation marker protein, suprabasin. SBSN_HUMAN[279-295] potently suppressed food/water intake and induced locomotor activity when injected intraperitoneally, while SBSN_HUMAN[225-237] and SBSN_HUMAN[243-259] stimulated the expression of proinflammatory cytokines via activation of NF-κB signaling in vascular cells. SBSN_HUMAN[225-237] and SBSN_HUMAN[279-295] immunoreactivities were present in almost all human organs analyzed, while immunoreactive SBSN_HUMAN[243-259] was abundant in the liver and pancreas. Human macrophages expressed the three suprabasin-derived peptides. This study illustrates a new approach for discovering unknown bioactive peptides in plasma via the generation of peptide libraries using a novel peptidomic strategy.
Collapse
Affiliation(s)
- Tomomi Taguchi
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Yoshio Kodera
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan ,grid.410786.c0000 0000 9206 2938Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Kazuhito Oba
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Tatsuya Saito
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan ,grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Yuzuru Nakagawa
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Yusuke Kawashima
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Masayoshi Shichiri
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| |
Collapse
|
|
8
|
Lu D, Wilson C, Littlewood TD. Methods for Determining Myc-Induced Apoptosis. Methods Mol Biol 2021; 2318:209-229. [PMID: 34019292 DOI: 10.1007/978-1-0716-1476-1_10] [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] [Indexed: 02/11/2024]
Abstract
Although many oncoproteins promote cell growth and proliferation, some also possess the potential to induce cell cycle arrest or cell death by apoptosis. Elevated and deregulated expression of the Myc protein promotes apoptosis in both cultured cells and in some tissues in vivo. Here we describe techniques to detect Myc-induced apoptosis in vitro using flow cytometry, microscopy, and immunoblotting, and in vivo using immunohistochemical staining, immunoblotting, and analysis of RNA expression.
Collapse
Affiliation(s)
- Dan Lu
- Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Catherine Wilson
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | | |
Collapse
|
|
9
|
Alam J, Sharma L. Potential Enzymatic Targets in Alzheimer's: A Comprehensive Review. Curr Drug Targets 2020; 20:316-339. [PMID: 30124150 DOI: 10.2174/1389450119666180820104723] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/23/2018] [Accepted: 08/15/2018] [Indexed: 12/13/2022]
Abstract
Alzheimer's, a degenerative cause of the brain cells, is called as a progressive neurodegenerative disease and appears to have a heterogeneous etiology with main emphasis on amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, that are directly linked with macromolecules called enzymes such as β- & γ-secretases, colinesterases, transglutaminases, and glycogen synthase kinase (GSK-3), cyclin-dependent kinase (cdk-5), microtubule affinity-regulating kinase (MARK). The catalytic activity of the above enzymes is the result of cognitive deficits, memory impairment and synaptic dysfunction and loss, and ultimately neuronal death. However, some other enzymes also lead to these dysfunctional events when reduced to their normal activities and levels in the brain, such as α- secretase, protein kinase C, phosphatases etc; metabolized to neurotransmitters, enzymes like monoamine oxidase (MAO), catechol-O-methyltransferase (COMT) etc. or these abnormalities can occur when enzymes act by other mechanisms such as phosphodiesterase reduces brain nucleotides (cGMP and cAMP) levels, phospholipase A2: PLA2 is associated with reactive oxygen species (ROS) production etc. On therapeutic fronts, several significant clinical trials are underway by targeting different enzymes for development of new therapeutics to treat Alzheimer's, such as inhibitors for β-secretase, GSK-3, MAO, phosphodiesterase, PLA2, cholinesterases etc, modulators of α- & γ-secretase activities and activators for protein kinase C, sirtuins etc. The last decades have perceived an increasing focus on findings and search for new putative and novel enzymatic targets for Alzheimer's. Here, we review the functions, pathological roles, and worth of almost all the Alzheimer's associated enzymes that address to therapeutic strategies and preventive approaches for treatment of Alzheimer's.
Collapse
Affiliation(s)
- Jahangir Alam
- School of Pharmaceutical Sciences, Shoolini University, Solan, H.P., Pin 173229, India
| | - Lalit Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan, H.P., Pin 173229, India
| |
Collapse
|
|
10
|
Harrington CT, Sotillo E, Robert A, Hayer KE, Bogusz AM, Psathas J, Yu D, Taylor D, Dang CV, Klein PS, Hogarty MD, Geoerger B, El-Deiry WS, Wiels J, Thomas-Tikhonenko A. Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma. Leukemia 2019; 33:2429-2441. [PMID: 30914792 PMCID: PMC6884148 DOI: 10.1038/s41375-019-0454-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023]
Abstract
Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. Considerable efforts have been expended toward silencing MYC, which drives many human cancers including Burkitt lymphomas (BL). Yet, the effects of MYC silencing on standard-of-care therapies are poorly understood. Here we found that inhibition of MYC transcription renders B-lymphoblastoid cells refractory to chemotherapeutic agents. This suggested that in the context of chemotherapy, stabilization of Myc protein could be more beneficial than its inactivation. We tested this hypothesis by pharmacologically inhibiting glycogen synthase kinase 3β (GSK-3β), which normally targets Myc for proteasomal degradation. We discovered that chemorefractory BL cell lines responded better to doxorubicin and other anti-cancer drugs when Myc was transiently stabilized. In vivo, GSK3 inhibitors (GSK3i) enhanced doxorubicin-induced apoptosis in BL patient-derived xenografts (BL-PDX), as well as in murine MYC-driven lymphoma allografts. This enhancement was accompanied by and required deregulation of several key genes acting in the extrinsic, death-receptor-mediated apoptotic pathway. Consistent with this mechanism of action, GSK3i also facilitated lymphoma cell killing by a death ligand TRAIL and by a death receptor agonist mapatumumab. Thus, GSK3i synergizes with both standard chemotherapeutics and direct engagers of death receptors and could improve outcomes in patients with refractory lymphomas.
Collapse
Affiliation(s)
- Colleen T Harrington
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Elena Sotillo
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Stanford Cancer Institute, 265 Campus Dr., Stanford, CA, 94305, USA
| | - Aude Robert
- CNRS UMR 8126, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France
| | - Katharina E Hayer
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Agata M Bogusz
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - James Psathas
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- The Janssen Pharmaceutical Companies of Johnson & Johnson, 200 Great Valley Parkway, Malvern, PA, 19355, USA
| | - Duonan Yu
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Noncoding RNA Center, Yangzhou University, 225001, Yangzhou, China
| | - Deanne Taylor
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Chi V Dang
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, 19104, USA
| | - Peter S Klein
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Michael D Hogarty
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Birgit Geoerger
- CNRS UMR 8203, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France
- Department of Pediatric and Adolescent Oncology, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France
| | - Wafik S El-Deiry
- Department of Pathology and Laboratory Medicine, Brown University Medical School, Providence, RI, 02912, USA
| | - Joëlle Wiels
- CNRS UMR 8126, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France
| | - Andrei Thomas-Tikhonenko
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
- Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
| |
Collapse
|
|
11
|
Wu Y, Xiao H, Pi J, Zhang H, Pan A, Pu Y, Liang Z, Shen J, Du J. EGFR promotes the proliferation of quail follicular granulosa cells through the MAPK/extracellular signal-regulated kinase (ERK) signaling pathway. Cell Cycle 2019; 18:2742-2756. [PMID: 31465245 DOI: 10.1080/15384101.2019.1656952] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Follicles develop into preovulatory follicles during folliculogenesis and the majority of small yellow follicles become atretic and gets reabsorbed. In this study, based the RNA-seq results of duck ovary, epidermal growth factor receptor (EGFR) was selected as a candidate gene in follicular development and the role was explored. The results demonstrated that EGFR-P8 was the quail EGFR core promoter. It had an E2F4 binding site within EGFR core promoter. E2F4 overexpression significantly increased EGFR expression in quail granulosa cells (GCs). However, the effect was abolished when the GCs were treated with corynoxeine, an inhibitor of the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) signaling pathway. Moreover, luciferase reporter assay and chromatin immunoprecipitation experiments showed that E2F4 upregulated the expression of EGFR expression, which increased E2 and P4 production. In addition, EGFR regulated GCs proliferation and affected follicular development. Taken together, our findings suggested that EGFR, which was regulated by E2F4, enhanced the expression of MAPK/ERK pathway components and follicular development. These results provided an important basis for an improved understanding of the MAPK/ERK pathway and new insight into the development of quail follicles.
Collapse
Affiliation(s)
- Yan Wu
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China.,Key Laboratory of Animal Embryo Engineering and Molecular Breeding of Hubei Province , Wuhan , China
| | - Hongwei Xiao
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| | - Jinsong Pi
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| | - Hao Zhang
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| | - Ailuan Pan
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| | - Yuejin Pu
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| | - Zhenhua Liang
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| | - Jie Shen
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| | - Jinping Du
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science , Wuhan , China
| |
Collapse
|
|
12
|
Zheng PY, Geng XR, Hong JY, Yang G, Liu JQ, Mo LH, Feng Y, Zhang YY, Liu T, Ran P, Liu ZG, Yang PC. Regulating Bcl2L12 expression in mast cells inhibits food allergy. Theranostics 2019; 9:4982-4992. [PMID: 31410196 PMCID: PMC6691383 DOI: 10.7150/thno.34001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/23/2019] [Indexed: 12/16/2022] Open
Abstract
Rationale: Mast cells play a crucial role in allergic diseases. Yet, the regulation of mast cell bioactivities is not fully understood. This study aims to elucidate the role of B cell lymphoma 2 like protein 12 (Bcl2L12), one of the anti-apoptosis proteins, in regulating mast cell apoptosis. Methods: A food allergy (FA) mouse model was developed to establish mast cell over population in the intestinal tissue. Either compound 48/80 (C48/80) or specific antigens were used to activate mast cells in the intestinal mucosa. Results: After treating with C48/80, apoptosis was induced in mast cells of the intestine of naive control mice, but not in FA mice. The expression of Fas ligand (FasL) was lower in the mast cells of FA mice. Interleukin (IL)-5 was responsible for the suppression of FasL by upregulating the expression of Bcl2L12 in mast cells. Bcl2L12 prevented c-Myc, the major transcription factor of FasL, from binding the FasL promoter to inhibit the expression of FasL in mast cells. Inhibition of Bcl2L12 restored the apoptosis machinery of mast cells in the FA mouse intestine. Conclusions: The apoptosis machinery in mast cells is impaired in an allergic environment. Inhibition of Bcl2L12 restores the apoptosis machinery in mast cells in the FA mouse intestine.
Collapse
Affiliation(s)
- Peng-Yuan Zheng
- Department of Gastroenterology, Fifth Hospital, Zhengzhou University, Zhengzhou, China
| | - Xiao-Rui Geng
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Jing-Yi Hong
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Department of Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Gui Yang
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Jiang-Qi Liu
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Li-Hua Mo
- Department of Pediatric Otolaryngology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Yan Feng
- Department of Otolaryngology, First Hospital and Nursing Collage, Shanxi Medical University, Taiyuan, China
| | - Yuan-Yi Zhang
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Tao Liu
- Department of Otolaryngology, First Hospital and Nursing Collage, Shanxi Medical University, Taiyuan, China
| | - Pixin Ran
- State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 510006, China
| | - Zhi-Gang Liu
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Ping-Chang Yang
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| |
Collapse
|
|
13
|
Bhavsar C, Momin M, Khan T, Omri A. Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies. Expert Opin Drug Deliv 2018; 15:641-663. [PMID: 29301448 DOI: 10.1080/17425247.2018.1424825] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Tumor is a heterogeneous mass of malignant cells co-existing with non-malignant cells. This co-existence evolves from the initial developmental stages of the tumor and is one of the hallmarks of cancer providing a protumorigenic niche known as tumor microenvironment (TME). Proliferation, invasiveness, metastatic potential and maintenance of stemness through cross-talk between tumors and its stroma forms the basis of TME. AREAS COVERED The article highlights the developmental phases of a tumor from dysplasia to the formation of clinically detectable tumors. The authors discuss the mechanistic stages involved in the formation of TME and its contribution in tumor outgrowth and chemoresistance. The authors have reviewed various approaches for targeting TME and its hallmarks along with their advantages and pitfalls. The authors also highlight cancer stem cells (CSCs) that are resistant to chemotherapeutics and thus a primary reason for tumor recurrence thereby, posing a challenge for the oncologists. EXPERT OPINION Recent understanding of the cellular and molecular mechanisms involved in acquired chemoresistance has enabled scientists to target the tumor niche and TME and modulate and/or disrupt this communication leading to the transformation from a tumor-supportive niche environment to a tumor-non-supporting environment and give synergistic results towards an effective management of cancer.
Collapse
Affiliation(s)
- Chintan Bhavsar
- a Department of Pharmaceutics, SVKMs Dr. Bhanuben Nanavati College of Pharmacy , University of Mumbai , Mumbai , India
| | - Munira Momin
- a Department of Pharmaceutics, SVKMs Dr. Bhanuben Nanavati College of Pharmacy , University of Mumbai , Mumbai , India
| | - Tabassum Khan
- b Department of Quality Assurance and Pharmaceutical Chemistry, SVKMs Dr. Bhanuben Nanavati College of Pharmacy , University of Mumbai , Mumbai , India
| | - Abdelwahab Omri
- c The Novel Drug & Vaccine Delivery Systems Facility, Department of Chemistry and Biochemistry , Laurentian University , Sudbury , ON , Canada
| |
Collapse
|
|
14
|
Guo X, Namekata K, Kimura A, Harada C, Harada T. ASK1 in neurodegeneration. Adv Biol Regul 2017; 66:63-71. [PMID: 28882588 DOI: 10.1016/j.jbior.2017.08.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/28/2017] [Accepted: 08/29/2017] [Indexed: 12/11/2022]
Abstract
Neurodegenerative diseases (NDDs) such as glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are characterized by the progressive loss of neurons, causing irreversible damage to patients. Longer lifespans may be leading to an increase in the number of people affected by NDDs worldwide. Among the pathways strongly impacting the pathogenesis of NDDs, oxidative stress, a condition that occurs because of an imbalance in oxidant and antioxidant levels, has been known to play a vital role in the pathophysiology of NDDs. One of the molecules activated by oxidative stress is apoptosis signal-regulating kinase 1 (ASK1), which has been shown to play a role in NDDs. ASK1 activation is regulated by multiple steps, including oligomerization, phosphorylation, and protein-protein interactions. In the oxidative stress state, reactive oxygen species (ROS) induce the dissociation of thioredoxin, a protein regulating cellular reduction and oxidation (redox), from the N-terminal region of ASK1, and ASK1 is subsequently activated by the oligomerization and phosphorylation of a critical threonine residue, leading to cell death. Here, we review experimental evidence that links ASK1 signaling with the pathogenesis of several NDDs. We propose that ASK1 may be a new point of therapeutic intervention to prevent or treat NDDs.
Collapse
Affiliation(s)
- Xiaoli Guo
- Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
| | - Kazuhiko Namekata
- Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Atsuko Kimura
- Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Chikako Harada
- Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Takayuki Harada
- Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| |
Collapse
|
|
15
|
Dasari S, Ali SM, Zheng G, Chen A, Dontaraju VS, Bosland MC, Kajdacsy-Balla A, Munirathinam G. Vitamin K and its analogs: Potential avenues for prostate cancer management. Oncotarget 2017; 8:57782-57799. [PMID: 28915711 PMCID: PMC5593683 DOI: 10.18632/oncotarget.17997] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 04/15/2017] [Indexed: 01/27/2023] Open
Abstract
Epidemiological studies have demonstrated a relationship between cancer incidence and dietary habits. Especially intake of certain essential nutrients like vitamins has been shown to be beneficial in experimental studies and some clinical trials. Vitamin K (VK) is an essential nutrient involved in the blood clotting cascade, and there are considerable experimental data demonstrating its potential anticancer activity in several cancer types including prostate cancer. Previous in vitro and in vivo studies have focused mainly on anti-oxidative effects as the underlying anticancer mechanism of VK. However, recent studies reveal that VK inhibits the growth of cancer cells through other mechanisms, including apoptosis, cell cycle arrest, autophagy, and modulation of various transcription factors such as Myc and Fos. In the present review, we focus on the anticancer effect of dietary VK and its analogs on prostate cancer, with an emphasis on the signaling pathways that are activated following exposure to these compounds. This review also highlights the potential of VK and its derivatives as an adjuvant treatment in combination with other vitamins or with chemotherapeutic drugs. Based on our recent results and a review of the existing literature, we present evidence that VK and its derivatives can potentially be explored as cancer therapy, especially for prostate cancer.
Collapse
Affiliation(s)
- Subramanyam Dasari
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL, USA
| | - Syed M Ali
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL, USA
| | - Guoxing Zheng
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL, USA
| | - Aoshuang Chen
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL, USA
| | | | - Maarten C Bosland
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Gnanasekar Munirathinam
- Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL, USA
| |
Collapse
|
|
16
|
Rodríguez-Frade JM, Guedán A, Lucas P, Martínez-Muñoz L, Villares R, Criado G, Balomenos D, Reyburn HT, Mellado M. Use of Lentiviral Particles As a Cell Membrane-Based mFasL Delivery System for In Vivo Treatment of Inflammatory Arthritis. Front Immunol 2017; 8:460. [PMID: 28484458 PMCID: PMC5399037 DOI: 10.3389/fimmu.2017.00460] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 04/04/2017] [Indexed: 12/18/2022] Open
Abstract
During budding, lentiviral particles (LVP) incorporate cell membrane proteins in the viral envelope. We explored the possibility of harnessing this process to generate LVP-expressing membrane proteins of therapeutic interest and studied the potential of these tools to treat different pathologies. Fas-mediated apoptosis is central to the maintenance of T cell homeostasis and prevention of autoimmune processes. We prepared LVP that express murine FasL on their surface. Our data indicate that mFasL-bearing LVP induce caspase 3 and 9 processing, cytochrome C release, and significantly more cell death than control LVP in vitro. This cytotoxicity is blocked by the caspase inhibitor Z-VAD. Analysis of the application of these reagents for the treatment of inflammatory arthritis in vivo suggests that FasL-expressing LVP could be useful for therapy in autoimmune diseases such as rheumatoid arthritis, where there is an excess of Fas-expressing activated T cells in the joint. LVP could be a vehicle not only for mFasL but also for other membrane-bound proteins that maintain their native conformation and might mediate biological activities.
Collapse
Affiliation(s)
- José M Rodríguez-Frade
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Anabel Guedán
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Pilar Lucas
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Laura Martínez-Muñoz
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Ricardo Villares
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Gabriel Criado
- Inflammatory and Autoimmune Diseases Group, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Dimitri Balomenos
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Hugh T Reyburn
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Mario Mellado
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| |
Collapse
|
|
17
|
Yuan Y, Kluiver J, Koerts J, de Jong D, Rutgers B, Abdul Razak FR, Terpstra M, Plaat BE, Nolte IM, Diepstra A, Visser L, Kok K, van den Berg A. miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1343-1355. [PMID: 28432871 DOI: 10.1016/j.ajpath.2017.02.016] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/16/2017] [Indexed: 12/11/2022]
Abstract
miRNAs play important roles in biological processes, such as proliferation, metabolism, differentiation, and apoptosis, whereas altered expression levels contribute to diseases, such as cancers. We identified miRNAs with aberrant expression in Hodgkin lymphoma (HL) and investigated their role in pathogenesis. Small RNA sequencing revealed 84 significantly differentially expressed miRNAs in HL cell lines as compared to germinal center B cells. Three up-regulated miRNAs-miR-23a-3p, miR-24-3p, and miR-27a-3p-were derived from one primary miRNA transcript. Loss-of-function analyses for these miRNAs and their seed family members resulted in decreased growth on miR-24-3p inhibition in three HL cell lines and of miR-27a/b-3p inhibition in one HL cell line. Apoptosis analysis indicated that the effect of miR-24-3p on cell growth is at least in part caused by an increase of apoptotic cells. Argonaute 2 immunoprecipitation revealed 1142 genes consistently targeted by miRNAs in at least three of four HL cell lines. Furthermore, 52 of the 1142 genes were predicted targets of miR-24-3p. Functional annotation analysis revealed a function related to cell growth, cell death, and/or apoptosis for 15 of the 52 genes. Western blotting of the top five genes showed increased protein levels on miR-24-3p inhibition for CDKN1B/P27kip1 and MYC. In summary, we showed that miR-24-3p is up-regulated in HL and its inhibition impairs cell growth possibly via targeting CDKN1B/P27kip1 and MYC.
Collapse
Affiliation(s)
- Ye Yuan
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - F Reeny Abdul Razak
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Martijn Terpstra
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Boudewijn E Plaat
- Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ilja M Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Lydia Visser
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
| |
Collapse
|
|
18
|
Nonomiya Y, Noguchi K, Tanaka N, Kasagaki T, Katayama K, Sugimoto Y. Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells. Cancer Sci 2016; 107:1877-1887. [PMID: 27699933 PMCID: PMC5198950 DOI: 10.1111/cas.13093] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/28/2016] [Accepted: 09/29/2016] [Indexed: 11/28/2022] Open
Abstract
Polo-like kinase (PLK) is a cell-cycle regulator that is overexpressed in several cancer cell types. Polo-like kinase is considered a novel target for cancer therapies, and several PLK inhibitors (PLKis), including BI 2536, BI 6727, and GSK461364, have been developed. In this study, we established five BI 2536-resistant cell lines from human colorectal cancer HCT 116 cells, to explore the resistance mechanism and identify predictable biomarkers of PLKis. We showed that PLKi-induced caspase-8 activation was attenuated in the BI 2536-resistant cell lines. We also showed that the expression of P-glycoprotein (P-GP) and AKT3 was upregulated, whereas that of MYC was downregulated in some BI 2536-resistant cell lines. Expression of P-GP conferred resistance to PLKis, and PLKi-induced apoptosis was dependent on MYC and caspase-8 in HCT 116 cells. We also showed for the first time that AKT3 suppressed BI 6727-induced caspase-8 activation and conferred resistance to PLKis. Collectively, these results indicate that MYC, caspase-8, P-GP, and AKT3 play critical roles in PLKi-induced apoptosis. Therefore, they are candidate biomarkers of the pharmacological efficacy of PLKis.
Collapse
Affiliation(s)
- Yuma Nonomiya
- Division of ChemotherapyFaculty of PharmacyKeio UniversityTokyoJapan
| | - Kohji Noguchi
- Division of ChemotherapyFaculty of PharmacyKeio UniversityTokyoJapan
| | - Noritaka Tanaka
- Division of ChemotherapyFaculty of PharmacyKeio UniversityTokyoJapan
| | - Takahiro Kasagaki
- Division of ChemotherapyFaculty of PharmacyKeio UniversityTokyoJapan
| | - Kazuhiro Katayama
- Division of ChemotherapyFaculty of PharmacyKeio UniversityTokyoJapan
| | | |
Collapse
|
|
19
|
Nagel R, Semenova EA, Berns A. Drugging the addict: non-oncogene addiction as a target for cancer therapy. EMBO Rep 2016; 17:1516-1531. [PMID: 27702988 PMCID: PMC5090709 DOI: 10.15252/embr.201643030] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 08/24/2016] [Indexed: 12/13/2022] Open
Abstract
Historically, cancers have been treated with chemotherapeutics aimed to have profound effects on tumor cells with only limited effects on normal tissue. This approach was followed by the development of small‐molecule inhibitors that can target oncogenic pathways critical for the survival of tumor cells. The clinical targeting of these so‐called oncogene addictions, however, is in many instances hampered by the outgrowth of resistant clones. More recently, the proper functioning of non‐mutated genes has been shown to enhance the survival of many cancers, a phenomenon called non‐oncogene addiction. In the current review, we will focus on the distinct non‐oncogenic addictions found in cancer cells, including synthetic lethal interactions, the underlying stress phenotypes, and arising therapeutic opportunities.
Collapse
Affiliation(s)
- Remco Nagel
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ekaterina A Semenova
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Anton Berns
- Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| |
Collapse
|
|
20
|
Sipos F, Firneisz G, Műzes G. Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases. World J Gastroenterol 2016; 22:7938-7950. [PMID: 27672289 PMCID: PMC5028808 DOI: 10.3748/wjg.v22.i35.7938] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host's protective immunity. In cells upon DNA damage several proto-oncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and micro-RNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be selected for combined regiments. However, due to its context-dependent cellular function, it is clinically essential to consider which cytotoxic drugs are used in combination with c-MYC targeted agents in various tissues. Increasing our knowledge about MYC-dependent pathways might provide direction to novel anti-inflammatory and colorectal cancer therapies.
Collapse
|
|
21
|
Negi AK, Bhatnagar A, Agnihotri N. Fish oil augments celecoxib mediated alteration in apoptotic pathway in the initiation phase of 7,12-dimethylbenz(α)anthracene-induced mammary carcinogenesis. Biomed Pharmacother 2016; 79:9-16. [PMID: 27044806 DOI: 10.1016/j.biopha.2016.01.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 01/22/2016] [Accepted: 01/25/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Resistance in apoptosis by disruption in signaling pathways is a common trait in malignancy. Celecoxib, a specific COX-2 inhibitor, has been reported to exert chemopreventive effect by inducing apoptosis. However, high doses or chronic usage of celecoxib for longer periods have various side effects. n-3 PUFA rich fish oil also abrogates COX-2 expression in tumors and thereby, has chemopreventive action. Combinatorial strategy using these two has been reported to be beneficial in mammary carcinoma. The present study was designed to understand the role of intrinsic and extrinsic apoptotic pathways in chemopreventive effect of celecoxib and fish oil in the initial phases of mammary carcinogenesis. METHODS Female Wistar rats were distributed into control and DMBA treated groups and further subdivided based on pretreatment with celecoxib and/or fish oil. The animals were subsequently maintained for 90 days and then sacrificed. The proteins involved in intrinsic and extrinsic pathways were assessed in isolated mammary epithelial cells using flowcytometry. RESULTS An increase in Bax, Bcl-2, Fas, FasL and caspase 8 levels was observed in DMBA treated animals. Celecoxib and/or fish oil further upregulate Bax, Fas, Fas L and caspase-8 while Bcl-2 levels were decreased. However maximal effect was observed with combinatorial dose of celecoxib and fish oil regimen. CONCLUSION Administration of a combinatorial therapy of fish oil and celecoxib in mammary carcinoma exert better chemopreventive effect by modulation of both intrinsic and extrinsic apoptotic pathways.
Collapse
Affiliation(s)
| | - Archana Bhatnagar
- Department of Biochemistry, Panjab University, Chandigarh 160014, India
| | - Navneet Agnihotri
- Department of Biochemistry, Panjab University, Chandigarh 160014, India.
| |
Collapse
|
|
22
|
Muthalagu N, Junttila MR, Wiese KE, Wolf E, Morton J, Bauer B, Evan GI, Eilers M, Murphy DJ. BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues. Cell Rep 2014; 8:1347-53. [PMID: 25176652 DOI: 10.1016/j.celrep.2014.07.057] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 06/04/2014] [Accepted: 07/30/2014] [Indexed: 11/30/2022] Open
Abstract
MYC is one of the most frequently overexpressed oncogenes in human cancer, and even modestly deregulated MYC can initiate ectopic proliferation in many postmitotic cell types in vivo. Sensitization of cells to apoptosis limits MYC's oncogenic potential. However, the mechanism through which MYC induces apoptosis is controversial. Some studies implicate p19ARF-mediated stabilization of p53, followed by induction of proapoptotic BH3 proteins NOXA and PUMA, whereas others argue for direct regulation of BH3 proteins, especially BIM. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used chemotherapeutic, doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined.
Collapse
Affiliation(s)
- Nathiya Muthalagu
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Melissa R Junttila
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 2356 Sutter Street, San Francisco, CA 94115, USA
| | - Katrin E Wiese
- Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Elmar Wolf
- Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Jennifer Morton
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Barbara Bauer
- Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Gerard I Evan
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 2356 Sutter Street, San Francisco, CA 94115, USA
| | - Martin Eilers
- Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Daniel J Murphy
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
| |
Collapse
|
|
23
|
Song J, Park KA, Lee WT, Lee JE. Apoptosis signal regulating kinase 1 (ASK1): potential as a therapeutic target for Alzheimer's disease. Int J Mol Sci 2014; 15:2119-2129. [PMID: 24481061 PMCID: PMC3958840 DOI: 10.3390/ijms15022119] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 01/20/2014] [Accepted: 01/21/2014] [Indexed: 01/10/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia, characterized by a decline in memory and cognitive function. Clinical manifestations of AD are closely associated with the formation of senile plaques and neurofibrillary tangles, neuronal loss and cognitive decline. Apoptosis signal regulating kinase 1 (ASK1) is a mediator of the MAPK pathway, which regulates various cellular responses such as apoptosis, cell survival, and differentiation. Accumulating evidence indicates that ASK1 plays a key role in the pathogenesis of neurodegenerative disorders such as Huntington's disease and AD. Of particular interest, ASK1 is associated with many signaling pathways, which include endoplasmic reticulum (ER) stress-mediated apoptosis, Aβ-induced neurotoxicity, tau protein phosphorylation, and insulin signal transduction. Here, we review experimental evidence that links ASK1 signaling and AD pathogenesis and propose that ASK1 might be a new point of therapeutic intervention to prevent or treat AD.
Collapse
Affiliation(s)
- Juhyun Song
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
| | - Kyung Ah Park
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
| | - Won Taek Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
| | - Jong Eun Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul 120-752, Korea.
| |
Collapse
|
|
24
|
Kim SH, Kang JG, Kim CS, Ihm SH, Choi MG, Yoo HJ, Lee SJ. Apigenin induces c-Myc-mediated apoptosis in FRO anaplastic thyroid carcinoma cells. Mol Cell Endocrinol 2013; 369:130-9. [PMID: 23376608 DOI: 10.1016/j.mce.2013.01.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2012] [Revised: 01/14/2013] [Accepted: 01/17/2013] [Indexed: 01/11/2023]
Abstract
Apigenin promotes apoptosis in cancer cells. We studied the effect of apigenin on cell survival and c-Myc expression in FRO anaplastic thyroid carcinoma (ATC) cells. Apigenin caused apoptosis via the elevation of c-Myc levels in conjunction with the phosphorylation of p38 and p53. In the c-Myc siRNA-transfected and apigenin-treated cells, compared with the apigenin-treated control cells, apoptosis and phosphorylation of p38 and p53 were ameliorated. In the presence of apigenin, diminution of p38 and p53 did not affect cell survival although apigenin activated the phosphorylation of p38 and p53 via increased c-Myc levels. In conclusion, our results indicate that apigenin induces apoptosis mediated via c-Myc with concomitant phosphorylation of p53 and p38 in FRO ATC cells. These findings suggest that augmented c-Myc acts as a core regulator and is necessary for apigenin-induced apoptosis in FRO ATC cells.
Collapse
Affiliation(s)
- Si Hyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon 200-704, Republic of Korea
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Morton JP, Sansom OJ. MYC-y mice: from tumour initiation to therapeutic targeting of endogenous MYC. Mol Oncol 2013; 7:248-58. [PMID: 23523308 PMCID: PMC5528411 DOI: 10.1016/j.molonc.2013.02.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 02/18/2013] [Indexed: 12/15/2022] Open
Abstract
MYC is one of the best-studied oncogenes in terms of mouse models of malignancy. MYC overexpression has been targeted to several tissues using transgenic constructs, and more recently as mouse models have evolved, conditional systems have been developed to allow the regulation of MYC expression or activity in vivo. The ability to target MYC expression to specific tissues and cell lineages, as well as the ability to regulate that expression, has made genetically engineered mouse models (GEMM) a valuable resource for studying the importance of MYC in the process of tumourigenesis. Here we review how these models have been used to address the role of MYC in tumour initiation and maintenance, how subtle changes in levels of MYC can influence tumourigenesis, and finally the ongoing efforts to target endogenous MYC genetically and with novel therapies.
Collapse
Affiliation(s)
- Jennifer P Morton
- Beatson Institute for Cancer Research, Garscube Estate, Switchback Rd, Glasgow G61 1BD, UK
| | | |
Collapse
|
|
26
|
Bannazadeh Amirkhiz M, Rashtchizadeh N, Nazemiyeh H, Abdolalizadeh J, Mohammadnejad L, Baradaran B. Investigating Apoptotic Effects of Methanolic Extract of Dorema glabrum Seed on WEHI-164 Cells. ISRN PHARMACOLOGY 2013; 2013:949871. [PMID: 23956872 PMCID: PMC3730363 DOI: 10.1155/2013/949871] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 06/11/2013] [Indexed: 04/30/2023]
Abstract
We aimed to investigate the apoptotic effects of the methanolic extract of Dorema glabrum seed on WEHI-164, cancerous cells in comparison with L929, normal cells and compared them with the cytotoxic effects of Taxol. So, MTT test and DNA fragmentation assay were performed on cultured and treated cells. Also electrophoresis which was followed by immunoblotting was done to survey the production of Caspase-3 and Bcl2 proteins, and to inquire into their relative genes expression, RT-PCR was used. According to our findings, the methanolic extract of Dorema glabrum seed can alter cells morphology as they shrink and take a spherical shape and lose their attachment too. So, the plant extract inhibits cell growth albeit in a time- and dose-dependent manner and results in degradation of chromosomal DNA. Induction of apoptosis by the plant extract was proved by the reduction of pro-Caspase-3 and Bcl2 proteins and increase in Caspase-3 gene expression and decrease in that of bcl2 too. Our data well established the antiproliferative effect of methanolic extract of Dorema glabrum seed and clearly showed that the plant extract can induce apoptosis and not necrosis in vitro. These results demonstrated that Dorema glabrum seed might be a novel and attractive therapeutic candidate for tumor treatment.
Collapse
Affiliation(s)
- Maryam Bannazadeh Amirkhiz
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
- Tabriz University of Medical Sciences, International Branch (Aras), Jolfa 5441643177, Iran
| | - Nadereh Rashtchizadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
- *Nadereh Rashtchizadeh: and
| | - Hossein Nazemiyeh
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Jalal Abdolalizadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Leila Mohammadnejad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
- *Behzad Baradaran:
| |
Collapse
|
|
27
|
Lu D, Littlewood TD. Methods for determining Myc-induced apoptosis. Methods Mol Biol 2013; 1012:85-98. [PMID: 24006060 DOI: 10.1007/978-1-62703-429-6_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Although many oncoproteins promote cell growth and proliferation, some also possess the potential to induce cell death by apoptosis. Deregulated expression of the myc oncogene promotes apoptosis in both cultured cells and in some tissues in vivo. Here we describe techniques to detect Myc-induced apoptosis in vitro using flow cytometry and microscopy and in vivo using immunohistochemical staining.
Collapse
Affiliation(s)
- Dan Lu
- Department of Biochemistry, University of Cambridge, Cambridge, UK
| | | |
Collapse
|
|
28
|
Wang DH, Hu JR, Wang LY, Hu YJ, Tan FQ, Zhou H, Shao JZ, Yang WX. The apoptotic function analysis of p53, Apaf1, Caspase3 and Caspase7 during the spermatogenesis of the Chinese fire-bellied newt Cynops orientalis. PLoS One 2012; 7:e39920. [PMID: 22768170 PMCID: PMC3386923 DOI: 10.1371/journal.pone.0039920] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Accepted: 05/29/2012] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Spontaneous and stress-induced germ cell apoptosis during spermatogenesis of multicellular organisms have been investigated broadly in mammals. Spermatogenetic process in urodele amphibians was essentially like that in mammals in spite of morphological differences; however, the mechanism of germ cell apoptosis in urodele amphibians remains unknown. The Chinese fire-belly newt, Cynops orientalis, was an excellent organism for studying germ cell apoptosis due to its sensitiveness to temperature, strong endurance of starvation, and sensitive skin to heavy metal exposure. METHODOLOGY/PRINCIPAL FINDINGS TUNEL result showed that spontaneous germ cell apoptosis took place in normal newt, and severe stress-induced apoptosis occurred to spermatids and sperm in response to heat shock (40°C 2 h), cold exposure (4°C 12 h), cadmium exposure (Cd 36 h), and starvation stress. Quantitative reverse transcription polymerase chain reactions (qRT-PCR) showed that gene expression of Caspase3 or Caspase7 was obviously elevated after stress treatment. Apaf1 was not altered at its gene expression level, and p53 was significantly decreased after various stress treatment. Caspase assay demonstrated that Caspase-3, -8, -9 enzyme activities in newt testis were significantly elevated after heat shock (40°C 2 h), cold exposure (4°C 12 h), and cadmium exposure (Cd 36 h), while Caspase3 and Caspase8 activities were increased with Caspase9 significantly decreased after starvation treatment. CONCLUSIONS/SIGNIFICANCE Severe germ cell apoptosis triggered by heat shock, cold exposure, and cadmium exposure was Caspase3 dependent, which probably involved both extrinsic and intrinsic pathways. Apaf1 may be involved in this process without elevating its gene expression. But starvation-induced germ cell apoptosis was likely mainly through extrinsic pathway. p53 was probably not responsible for stress-induced germ cell apoptosis in newt testis. The intriguing high occurrence of spermatid and sperm apoptosis probably resulted from the sperm morphology and unique reproduction policy of Chinese fire-belly newt, Cynops orientalis.
Collapse
Affiliation(s)
- Da-Hui Wang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Jian-Rao Hu
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, People's Republic of China
| | - Li-Ya Wang
- Department of Reproductive Endocrinology, The Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Yan-Jun Hu
- Department of Reproductive Endocrinology, The Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Fu-Qing Tan
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Hong Zhou
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Jian-Zhong Shao
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Wan-Xi Yang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, People's Republic of China
| |
Collapse
|
|
29
|
Fennell DA, Swanton C. Unlocking Pandora's box: personalising cancer cell death in non-small cell lung cancer. EPMA J 2012; 3:6. [PMID: 22738201 PMCID: PMC3422179 DOI: 10.1186/1878-5085-3-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 05/03/2012] [Indexed: 01/09/2023]
Abstract
Evasion of apoptosis is a hallmark of tumorigenesis and a recognised cause of multidrug resistance. Over the last decade, insights into how apoptosis might be exploited in non-small cell lung cancer (NSCLC) and how cancer therapeutics might be used to engage apoptotic signalling in a personalised manner have changed markedly. We are now in the wake of a paradigm shift in stratified therapeutic approaches related to NSCLC. At the heart of this shift in thinking is the emerging knowledge that even the most drug-resistant cancers exhibit a functional death pathway and, critically, that this pathway can be efficiently engaged, leading to clinical benefit. This review will summarise current knowledge of mitochondrial apoptotic pathway dysfunction in NSCLC and how the next generation of targeted therapeutics might be used to exploit deficiencies in apoptotic signalling in a personalised manner to improve clinical outcome and predict therapeutic benefit.
Collapse
Affiliation(s)
- Dean A Fennell
- University of Leicester & Leicester University Hospitals, Hodgkin Building, Lancaster Road, PO Box 138, Leicester, LE1 9HN, UK.
| | | |
Collapse
|
|
30
|
Hiyama A, Sakai D, Arai F, Nakajima D, Yokoyama K, Mochida J. Effects of a glycogen synthase kinase-3β inhibitor (LiCl) on c-myc protein in intervertebral disc cells. J Cell Biochem 2012; 112:2974-86. [PMID: 21678465 DOI: 10.1002/jcb.23217] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Wnt/β-catenin (hereafter called Wnt) signaling is a key inducer and regulator of joint development, and is involved in the formation of bone and cartilage. We previously reported that Wnt signaling plays an essential role in the control of cell proliferation and cell senescence in intervertebral disc cells. In the present study, we provide evidence that the expression of c-myc, a key protein required for cell proliferation, is regulated by Wnt signaling. Our data also show that activation of Wnt signaling by LiCl, a Wnt signaling activator, leads to the suppression of c-myc promoter activity and expression. To ascertain whether Wnt signaling regulates the expression of c-myc, we measured both its transcript and protein expression. Following treatment with LiCl, c-myc expression was suppressed at both the mRNA and protein levels. In nucleus pulposus cells treated with c-myc, cell viability increased significantly, whereas treatment with a c-myc inhibitor decreased cell viability. Taken together, these results suggest that c-myc is an important factor that promotes the proliferation of nucleus pulposus cells. These findings provide new insight into the regulation and maintenance of cell proliferation in nucleus pulposus cells.
Collapse
Affiliation(s)
- Akihiko Hiyama
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
| | | | | | | | | | | |
Collapse
|
|
31
|
Högstrand K, Hejll E, Sander B, Rozell B, Larsson LG, Grandien A. Inhibition of the intrinsic but not the extrinsic apoptosis pathway accelerates and drives MYC-driven tumorigenesis towards acute myeloid leukemia. PLoS One 2012; 7:e31366. [PMID: 22393362 PMCID: PMC3290626 DOI: 10.1371/journal.pone.0031366] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Accepted: 01/09/2012] [Indexed: 11/18/2022] Open
Abstract
Myc plays an important role in tumor development, including acute myeloid leukemia (AML). However, MYC is also a powerful inducer of apoptosis, which is one of the major failsafe programs to prevent cancer development. To clarify the relative importance of the extrinsic (death receptor-mediated) versus the intrinsic (mitochondrial) pathway of apoptosis in MYC-driven AML, we coexpressed MYC together with anti-apoptotic proteins of relevance for AML; BCL-X(L)/BCL-2 (inhibiting the intrinsic pathway) or FLIP(L) (inhibiting the extrinsic pathway), in hematopoietic stems cells (HSCs). Transplantation of HSCs expressing MYC into syngeneic recipient mice resulted in development of AML and T-cell lymphomas within 7-9 weeks as expected. Importantly, coexpression of MYC together with BCL-X(L)/BCL-2 resulted in strongly accelerated kinetics and favored tumor development towards aggressive AML. In contrast, coexpression of MYC and FLIP(L) did neither accelerate tumorigenesis nor change the ratio of AML versus T-cell lymphoma. However, a change in distribution of immature CD4(+)CD8(+) versus mature CD4(+) T-cell lymphoma was observed in MYC/FLIP(L) mice, possibly as a result of increased survival of the CD4+ population, but this did not significantly affect the outcome of the disease. In conclusion, our findings provide direct evidence that BCL-X(L) and BCL-2 but not FLIP(L) acts in synergy with MYC to drive AML development.
Collapse
Affiliation(s)
- Kari Högstrand
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Eduar Hejll
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Birgitta Sander
- Divisions of Clinical Research Center and Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Björn Rozell
- Divisions of Clinical Research Center and Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Lars-Gunnar Larsson
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Alf Grandien
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- * E-mail:
| |
Collapse
|
|
32
|
Järvinen K, Hotti A, Santos L, Nummela P, Hölttä E. Caspase-8, c-FLIP, and caspase-9 in c-Myc-induced apoptosis of fibroblasts. Exp Cell Res 2011; 317:2602-15. [DOI: 10.1016/j.yexcr.2011.08.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Revised: 08/10/2011] [Accepted: 08/22/2011] [Indexed: 01/02/2023]
|
|
33
|
Kim HB, Kim MJ, Kim DY, Lee JW, Bae JH, Kim DW, Kang CD, Kim SH. High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy-2-nitrobenzaldehyde. Mol Cancer 2011; 10:46. [PMID: 21513580 PMCID: PMC3094320 DOI: 10.1186/1476-4598-10-46] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2010] [Accepted: 04/25/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tumor recurrence and metastasis develop as a result of tumors' acquisition of anti-apoptotic mechanisms and therefore, it is necessary to develop novel effective therapeutics against metastatic cancers. In this study, we showed the differential TRAIL responsiveness of human prostate adenocarcinoma PC3 and human colon carcinoma KM12 cells and their respective highly metastatic PC3-MM2 and KM12L4A sublines and investigated the mechanism underlying high susceptibility of human metastatic cancer cells to TRAIL. RESULTS PC3-MM2 and KM12L4A cells with high level of c-Myc and DNA-PKcs were more susceptible to TRAIL than their poorly metastatic primary PC3 and KM12 cells, which was associated with down-regulation of c-FLIPL/S and Mcl-1 and up-regulation of the TRAIL receptor DR5 but not DR4 in both metastatic cells. Moreover, high susceptibility of these metastatic cells to TRAIL was resulted from TRAIL-induced potent activation of caspase-8, -9, and -3 in comparison with their primary cells, which led to cleavage and down-regulation of DNA-PKcs. Knockdown of c-Myc gene in TRAIL-treated PC3-MM2 cells prevented the increase of DR5 cell surface expression, caspase activation and DNA-PKcs cleavage and attenuated the apoptotic effects of TRAIL. Moreover, the suppression of DNA-PKcs level with siRNA in the cells induced the up-regulation of DR5 and active caspase-8, -9, and -3. We also found that 4,5-dimethoxy-2-nitrobenzaldehyde (DMNB), a specific inhibitor of DNA-PK, potentiated TRAIL-induced cytotoxicity and apoptosis in relatively TRAIL-insensitive PC3 and KM12 cells and therefore functioned as a TRAIL sensitizer. CONCLUSION This study showed the positive relationship between c-Myc expression in highly metastatic human prostate and colon cancer cells and susceptibility to TRAIL-induced apoptosis and therefore indicated that TRAIL might be used as an effective therapeutic modality for advanced metastatic cancers overexpressing c-Myc and combination of TRAIL therapy with agent that inhibits the DNA-PKcs/Akt signaling pathway might be clinically useful for the treatment of relatively TRAIL-insensitive human cancers.
Collapse
Affiliation(s)
- Hak-Bong Kim
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, South Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Li F, He Z, Shen J, Huang Q, Li W, Liu X, He Y, Wolf F, Li CY. Apoptotic caspases regulate induction of iPSCs from human fibroblasts. Cell Stem Cell 2011; 7:508-20. [PMID: 20887956 DOI: 10.1016/j.stem.2010.09.003] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 06/03/2010] [Accepted: 09/08/2010] [Indexed: 01/01/2023]
Abstract
The molecular mechanisms involved in the derivation of induced pluripotent stem cells (iPSCs) from differentiated cells are poorly understood. Here we report that caspases 3 and 8, two proteases associated with apoptotic cell death, play critical roles in induction of iPSCs from human fibroblasts. Activation of caspases 3 and 8 occurs soon after transduction of iPSC-inducing transcription factors. Oct-4, a key iPSC transcription factor, is responsible for the activation. Inhibition of caspase 3 or 8 in human fibroblast cells partially or completely (respectively) prevents the induction of iPSCs. Furthermore, retinoblastoma susceptibility (Rb) protein appears to be one of the factors that act downstream of the caspases. We propose that caspases are key facilitators of nuclear reprogramming in iPSC induction.
Collapse
Affiliation(s)
- Fang Li
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Xu B, Xu Z, Xia T, He P, Gao P, He W, Zhang M, Guo L, Niu Q, Wang A. Effects of the Fas/Fas-L pathway on fluoride-induced apoptosis in SH-SY5Y cells. ENVIRONMENTAL TOXICOLOGY 2011; 26:86-92. [PMID: 19852076 DOI: 10.1002/tox.20543] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
The mechanisms underlying fluoride-induced apoptosis in neurons still remain unknown. To investigate apoptosis, caspase-3 activity, and mRNA expression of Fas, Fas-L, and caspases (-3 and -8) induced by fluoride, human neuroblastoma (SH-SY5Y) cells were incubated with 0, 20, 40, and 80 mg/L sodium fluoride (NaF) for 24 h in vitro. The data show that cell viability in the 40 and 80 mg/L fluoride groups were significantly lower than that of the control group. The percentages of apoptosis in the 40 and 80 mg/L fluoride groups were markedly higher than those in the control group, and they increased with the increase in fluoride concentration. The activity of caspase-3 and mRNA expression levels for Fas, Fas-L, and caspases (-3 and -8) in the 40 and 80 mg/L fluoride groups were significantly higher than those in the control group. An agonistic anti-Fas monoclonal antibody (CH-11) significantly augmented apoptosis induction by fluoride, showing a synergistic effect, while a Fas-blocking antibody (ZB4) partly inhibited fluoride-induced apoptosis of SH-SY5Y cells. The results indicate that fluoride exposure could induce apoptosis in SH-SY5Y cells, and the Fas/Fas-L signaling pathway may play an important role in the process.
Collapse
Affiliation(s)
- Bayi Xu
- MOE Key Lab of Environment and Health, Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, Hubei, People's Republic of China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Aberg M, Johnell M, Wickström M, Siegbahn A. Tissue Factor/ FVIIa prevents the extrinsic pathway of apoptosis by regulation of the tumor suppressor Death-Associated Protein Kinase 1 (DAPK1). Thromb Res 2010; 127:141-8. [PMID: 21168190 DOI: 10.1016/j.thromres.2010.11.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 10/24/2010] [Accepted: 11/15/2010] [Indexed: 11/26/2022]
Abstract
INTRODUCTION This study determines the impact of tissue factor (TF)-signaling on the extrinsic pathway of apoptosis in cancer cells and propose death associated protein kinase-1 (DAPK1) as a novel key regulator. MATERIALS AND METHODS In MDA-MB-231 breast and PC3 prostate cancer cells, mRNA levels were analyzed by real-time PCR and protein expressions were assessed by flow cytometry or western blot. Caspase-8 and -3 levels, cell size, and changes in nuclear morphology were recorded using the ArrayScan microscope and 84 apoptosis-related genes were screened with the RT2 Profiler™ PCR Array. RESULTS In serum starved MDA-MB-231 cells, a TF/FVIIa-sensitive upregulation of apoptosis markers was recorded. Similarly, TRAIL-induced apoptosis was negatively regulated by TF/FVIIa (10 and 100 nM) and TF/FVIIa/FXa but not by active-site inhibited FVIIa. FVIIa, moreover, decreased the transcription of DAPK1 and thereby diminished the association between DAPK1 and FADD in the caspase-8 activating death-inducing signaling complex (DISC). TF/FVIIa regulation of caspase-8 and DAPK1 was dependent on PI3-kinase/AKT and independent of the protease activated receptors (PAR) 1 and 2. Despite of receptor expression and functional signaling, both PAR-agonist treatment and PAR-blocking antibodies in combination with FVIIa failed to influence the anti-apoptotic signal. CONCLUSIONS We hereby report that TF/FVIIa-induced signaling governs the extrinsic pathway of apoptosis by reducing the levels of DAPK1 in the DISC independently of PAR1 and PAR2. This implies the conceivable involvement of cell surface components other than the PARs and entails the search for TF-dependent regulators of DAPK1 transcription.
Collapse
Affiliation(s)
- M Aberg
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.
| | | | | | | |
Collapse
|
|
37
|
Abstract
Up to 70% of all human malignancies show elevated expression of MYC. MYC is a pleiotropic transcription factor involved in many aspects of cellular development and physiology. Besides direct regulation of target genes involved in proliferation and growth MYC is implicated in controlling the complex networks of microRNAs and apoptosis mediators. The mode of MYC deregulation varies between different tumor entities. In most types of cancer high MYC levels are secondary to alterations in cell signalling pathways, leading to enhanced proliferation of the transformed cells. In some haematological malignancies, like Burkitt lymphoma (BL) and subsets of diffuse large B-cell lymphomas, elevated MYC levels are a direct consequence of genomic aberrations involving the MYC locus. BL is considered the prime example for MYC-induced lymphomagenesis. In comparison to other haematological malignancies it has the highest MYC-expression and is often connected to Epstein-Barr virus (EBV) infection. Over the past five decades BL has provided an invaluable tool for the entire discipline of oncology, helping to decipher many aspects of tumor biology. This review summarizes recent advances in the research on MYC-induced lymphomagenesis, focusing on the regulation of microRNAs and apoptosis, and possible contributions of EBV for lymphoma development.
Collapse
Affiliation(s)
- Kay Klapproth
- Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
| | | |
Collapse
|
|
38
|
Bernier-Dodier P, Delbecchi L, Wagner G, Talbot B, Lacasse P. Effect of milking frequency on lactation persistency and mammary gland remodeling in mid-lactation cows. J Dairy Sci 2010; 93:555-64. [DOI: 10.3168/jds.2009-2320] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Accepted: 10/07/2009] [Indexed: 11/19/2022]
|
|
39
|
Sala A, Bettuzzi S, Pucci S, Chayka O, Dews M, Thomas-Tikhonenko A. Regulation of CLU gene expression by oncogenes and epigenetic factors implications for tumorigenesis. Adv Cancer Res 2010; 105:115-32. [PMID: 19879426 DOI: 10.1016/s0065-230x(09)05007-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
In no other field has the function of clusterin (CLU) been more controversial than in cancer genetics. After more than 20 years of research, there is still uncertainty with regard to the role of CLU in human cancers. Some investigators believe CLU to be an oncogene, others-an inhibitor of tumorigenesis. However, owing to the recent efforts of several laboratories, the role of CLU in important cellular processes like proliferation, apoptosis, differentiation, and transformation is beginning to emerge. The "enigmatic" CLU is becoming less so. In this chapter, we will review the work of research teams interested in understanding how CLU is regulated by oncogenic signaling. We will discuss how and under what circumstances oncogenes and epigenetic factors modify CLU expression, with important consequences for mammalian tumorigenesis.
Collapse
Affiliation(s)
- Arturo Sala
- Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, United Kingdom
| | | | | | | | | | | |
Collapse
|
|
40
|
AP-2alpha Inhibits c-MYC Induced Oxidative Stress and Apoptosis in HaCaT Human Keratinocytes. JOURNAL OF ONCOLOGY 2009; 2009:780874. [PMID: 20066163 PMCID: PMC2801504 DOI: 10.1155/2009/780874] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2009] [Accepted: 10/02/2009] [Indexed: 01/03/2023]
Abstract
AP-2α and c-MYC are important transcription factors involved in multiple cellular processes. They each display the paradoxical capacities to stimulate both cell proliferation and apoptosis under different conditions. In the present study we found that over expression of c-MYC was associated with accumulation of reactive oxygen species (ROS) and apoptosis in human keratinocytes, both of which were significantly inhibited by co-expression of AP-2. The effects of AP-2 on c-MYC were active at several levels. First, AP-2 and c-MYC were confirmed to interact at the protein level as previously described. In addition, forced expression of AP-2 significantly decreased steady state levels of c-MYC mRNA and protein. These findings suggested that
AP-2 may have a direct effect on the c-myc gene. Chromatin immunoprecipitation assays demonstrated that AP-2 proteins bound to a cluster of AP-2 binding sites located within a 2 kb upstream regulatory region of c-myc These results suggest that the negative regulation of AP-2 on c-MYC activity was achieved through binding of AP-2 protein to the c-myc gene. The effects of AP-2 on c-MYC induced ROS accumulation and apoptosis in epidermal keratinocytes are likely to play an important role in cell growth, differentiation and carcinogenesis of the skin.
Collapse
|
|
41
|
Zhang M, Abe Y, Matsushima T, Nishimura J, Nawata H, Muta K. Selective cyclooxygenase 2 inhibitor NS-398 induces apoptosis in myeloma cells via a Bcl-2 independent pathway. Leuk Lymphoma 2009; 46:425-33. [PMID: 15621834 DOI: 10.1080/10428190400015691] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
NS-398, a selective inhibitor of cyclooxygenase 2 (COX-2), has been reported to inhibit growth and induce apoptosis in several cancer cell lines that overexpress COX-2. However it has not been extensively studied in multiple myeloma (MM). Here, we studied the effects of COX-2 inhibitors on MM cell lines and primary myeloma patient cells. We investigated the effects of NS-398 on proliferation and apoptosis in three myeloma cell lines (PCM6, U266 and RPMI8226) and isolated CD138-positive cells from MM patients. Furthermore, the combined effects of NS-398 plus dexamethasone (Dex) or thalidomide (Thal) were investigated. All myeloma cell lines express COX-2. NS-398 inhibited growth and induced apoptosis in PCM6, RPMI8226 and CD138-positive MM cells in a time- and dose-dependent manner. At low concentrations (10 microM), NS-398 primarily induced growth arrest without affecting cell viability, but at higher concentrations (over 25 microM), apoptosis was induced. During the process of apoptosis, the number of Fas-positive cells increased. Downstream signals of Fas, such as caspase 8, 3 and 9, were also activated. On the other hand, protein levels of the Bcl-2 family did not change, although mitochondrial transmembrane potential ((Delta)(psi)m) was decreased. Combined incubation with Dex or Thal enhanced NS-398-induced growth inhibition and apoptosis in RPMI8226 cells. The combined effect of Dex was more potent than that of Thal. Our findings suggests that COX-2 plays an important role in regulation of apoptosis in myeloma cells, and COX-2 inhibitors might serve as an effective tool for future chemoprevention and/or treatment of myeloma.
Collapse
Affiliation(s)
- Min Zhang
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | | | | | | | | |
Collapse
|
|
42
|
Peluffo MC, Young KA, Hennebold JD, Stouffer RL. Expression and regulation of tumor necrosis factor (TNF) and TNF-receptor family members in the macaque corpus luteum during the menstrual cycle. Mol Reprod Dev 2009; 76:367-78. [PMID: 18932199 DOI: 10.1002/mrd.20970] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Members of the tumor necrosis factor (TNF)-receptor (R) family may be involved in the tissue remodeling that occurs in the primate corpus luteum (CL) during development and regression. As a first step towards addressing this issue, studies assessed TNF ligand-R expression and regulation in CL collected from monkeys during the early (ECL, Days 3-5), mid (MCL, Days 7-8), mid-late (MLCL, Days 10-11), late (LCL, Days 14-16), and very late (VLCL, menses) luteal phase of the menstrual cycle. CL were also collected after gonadotropin and/or steroid ablation and replacement (with hLH and the progestin R5020) for 3 days at mid-late luteal phase. TNF-alpha, -beta, FAS ligand (FASL), and TNF-R1 mRNA levels were two- to sixfold greater (P < 0.05) at the MLCL or LCL phase as compared to earlier (ECL, MCL). In contrast, TNF-R2 and FAS mRNA levels did not change during the luteal phase. Immunohistochemical staining for TNF-beta, TNF-R1, TNF-R2, FAS, and FASL was observed in luteal cells, whereas only TNF-beta staining was observed in endothelial cells. Several TNF-R components were influenced by LH and/or steroid ablation; notably, steroid ablation reduced (P < 0.05) luteal TNF-alpha, but not TNF-beta, mRNA levels, which was prevented by progestin treatment. In contrast, steroid ablation increased (P < 0.05) luteal cell immunostaining for FAS and FASL, which was reduced by progestin treatment. Thus, several members of the TNF R-ligand family are expressed in the primate CL in an LH- and/or progestin-dependent manner. Peak expression in the late luteal phase may signify a role for the TNF-R system in death receptor-mediated apoptosis during luteolysis.
Collapse
Affiliation(s)
- Marina C Peluffo
- Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA
| | | | | | | |
Collapse
|
|
43
|
Shen C, Zhou Y, Zhan J, Reske SN, Buck AK. Chromosome instability and tumor lethality suppression in carcinogenesis. J Cell Biochem 2008; 105:1327-41. [DOI: 10.1002/jcb.21937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
|
|
44
|
Abstract
c-MYC has a pivotal function in growth control, differentiation and apoptosis, and its abnormal expression is associated with many tumors. Overexpression of c-MYC sensitizes cells to apoptosis by a variety of stimuli. The decision of a cell to undergo apoptosis and how this apoptotic response is regulated by c-MYC depends on the specific cell type and the physiological status of the cell. Multiple cooperating molecular pathways of cell survival and apoptosis determine whether a cell lives or dies, and understanding how c-MYC interfaces with these pathways to influence the survival of cells is important to understand normal and abnormal development, tumor initiation and progression, and response of tumors to different treatment regimens. This article will provide an overview of the function of the tumor suppressor gene product p53 in the c-MYC-mediated apoptotic response and how c-MYC amplifies the intrinsic mitochondrial pathway and triggers and/or amplifies the death receptor pathways. Finally, a model for how deregulated c-MYC prematurely triggers the normal apoptotic response associated with terminal myeloid differentiation while also blocking the differentiation program is presented.
Collapse
|
|
45
|
Patra SK, Szyf M. DNA methylation-mediated nucleosome dynamics and oncogenic Ras signaling: insights from FAS, FAS ligand and RASSF1A. FEBS J 2008; 275:5217-35. [PMID: 18803665 DOI: 10.1111/j.1742-4658.2008.06658.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cytosine methylation at the 5-carbon position is the only known stable base modification found in the mammalian genome. The organization and modification of chromatin is a key factor in programming gene expression patterns. Recent findings suggest that DNA methylation at the junction of transcription initiation and elongation plays a critical role in suppression of transcription. This effect is mechanistically mediated by the state of chromatin modification. DNA methylation attracts binding of methyl-CpG-binding domain proteins that trigger repression of transcription, whereas DNA demethylation facilitates transcription activation. Understanding the rules that guide differential gene expression, as well as transcription dynamics and transcript abundance, has proven to be a taxing problem for molecular biologists and oncologists alike. The use of novel molecular modeling methods is providing exciting insights into the challenging problem of how methylation mediates chromatin dynamics. New data implicate lipid rafts as the coordinators of signals emanating from the cell membrane and are converging on the mechanisms linking DNA methylation and chromatin dynamics. This review focuses on some of these recent advances and uses lipid-raft-facilitated Ras signaling as a paradigm for understanding DNA methylation, chromatin dynamics and apoptosis.
Collapse
|
|
46
|
Martin D, Lenardo M. Morphological, biochemical, and flow cytometric assays of apoptosis. ACTA ACUST UNITED AC 2008; Chapter 14:Unit 14.13. [PMID: 18265108 DOI: 10.1002/0471142727.mb1413s49] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
As programmed cell death (PCD), or apoptosis, has emerged as an important regulator of development and homeostasis in multicellular organisms, methods to quantify apoptosis and to distinguish it from necrosis have been developed. Necrosis refers to the morphology usually associated with accidental cell death, while apoptosis is seen when cell death is programmed or physiologically regulated. This unit presents a set of assays for these purposes, many of which are technically very simple. Featured in this unit is the TUNEL method of detecting cells that exhibit DNA fragmentation, which can also be performed on tissue sections to locate apoptotic cells in situ.
Collapse
Affiliation(s)
- D Martin
- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | | |
Collapse
|
|
47
|
Liu XY, Guo GH, Duan XM, Chen J, Cao JG, He XS. Effect of anti-sense c-myc oligodeoxynucleotide on MKN28 gastric cancer cells transfected with FHIT gene. Shijie Huaren Xiaohua Zazhi 2008; 16:240-245. [DOI: 10.11569/wcjd.v16.i3.240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect of anti-sense c-myc oligodeoxynucleotide on the proliferation and apoptosis of gastric cancer cells transfected with the Frogile histindine triad (FHIT) gene.
METHODS: The FHIT gene was transfected into human gastric cancer MKN28 cells through liposomes. The antis-sense c-myc oligodeoxynucleotide was transfected into the FHIT gene. FHIT gene transfection was detected by RT-PCR and Western blot. Expression of c-myc was detected by Western blot. Proliferation of gastric cancer cells was determined by MTT. Cell apoptosis was detected by AO/EB staining and FCM.
RESULTS: The expression of MKN28 cells transfected with the FHIT gene was observed. However, no FHIT gene segment and FHIT protein were found in the cells transfected with void vector. C-myc transfected with the FHIT gene exhibited significant inhibitory effects on the expression of c-myc protein in MKN28 cells and induced cell apoptosis in a time-dependent manner. However, the inhibition rate (F = 177.480, P < 0.05) (F = 41.500, P < 0.05), apoptosis rate, and apoptosis portion of anti-sense c-myc oligodeoxynucleotide for C-myc were higher than those for FHIT+ MKN28 cells.
CONCLUSION: The expression of c-myc and FHIT oncogenes plays an important role in suppressing the growth of tumor cells and may provide the theoretical basis for the gene therapy of tumors.
Collapse
|
|
48
|
N-myc augments death and attenuates protective effects of Bcl-2 in trophically stressed neuroblastoma cells. Oncogene 2008; 27:3424-34. [PMID: 18193081 DOI: 10.1038/sj.onc.1211017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
N-myc has proapoptotic functions, yet it acts as an oncogene in neuroblastoma. Thus, antiapoptotic mechanisms have to be operative in neuroblastoma cells that antagonize the proapoptotic effects of N-myc. We conditionally activated N-myc in SH-EP neuroblastoma cells subjected to the trophic stress of serum or nutrient deprivation while changing the expression of Bcl-2, survivin and FLIP(L), antiapoptotic molecules often overexpressed in poor prognosis neuroblastomas. Bcl-2 protected SH-EP cells from death during nutritional deprivation by activating energetically advantageous oxidative phosphorylation. N-myc overrode the metabolic protection provided by Bcl-2-induced oxidative phosphorylation by reestablishing the glycolytic phenotype and attenuated the antiapoptotic effect of Bcl-2 during metabolic stress. Survivin partially antagonized the growth suppressive function of N-myc in SH-EP neuroblastoma cells during serum deprivation whereas FLIP(L) did not. These findings advance our understanding of the functions of N-myc in neuroblastoma cells.
Collapse
|
|
49
|
Maddika S, Bay GH, Kroczak TJ, Ande SR, Maddika S, Wiechec E, Gibson SB, Los M. Akt is transferred to the nucleus of cells treated with apoptin, and it participates in apoptin-induced cell death. Cell Prolif 2007; 40:835-48. [PMID: 18021174 DOI: 10.1111/j.1365-2184.2007.00475.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVES The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is well known for the regulation of cell survival, proliferation, and some metabolic routes. MATERIALS AND METHODS In this study, we document a novel role for the PI3-K/Akt pathway during cell death induced by apoptin, a tumour-selective inducer of apoptosis. RESULTS We show for the first time that apoptin interacts with the p85 regulatory subunit, leading to constitutive activation of PI3-K. The inhibition of PI3-K activation either by chemical inhibitors or by genetic approaches severely impairs cell death induced by apoptin. Downstream of PI3-K, Akt is activated and translocated to the nucleus together with apoptin. Direct interaction between apoptin and Akt is documented. Co-expression of nuclear Akt significantly potentiates cell death induced by apoptin. Thus, apoptin-facilitated nuclear Akt, in contrast to when in its cytoplasmic pool, appears to be a positive regulator, rather than repressor of apoptosis. CONCLUSIONS Our observations indicate that PI3-K/Akt pathways have a dual role in both survival and cell death processes depending on the stimulus. Nuclear Akt acts as apoptosis stimulator rather than as a repressor, as it likely gains access to a new set of substrates in the nucleus. The implicated link between survival and cell death pathways during apoptosis opens new pharmacological opportunities to modulate apoptosis in cancer, for example through the manipulation of Akt's cellular localization.
Collapse
Affiliation(s)
- S Maddika
- Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Canada
| | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Patra SK. Dissecting lipid raft facilitated cell signaling pathways in cancer. Biochim Biophys Acta Rev Cancer 2007; 1785:182-206. [PMID: 18166162 DOI: 10.1016/j.bbcan.2007.11.002] [Citation(s) in RCA: 152] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2007] [Revised: 11/24/2007] [Accepted: 11/29/2007] [Indexed: 01/09/2023]
Abstract
Cancer is one of the most devastating disorders in our lives. Higher rate of proliferation than death of cells is one of the essential factors for development of cancer. The dynamicity of cell membrane plays some vital roles in cell survival and cell death, including protection, endocytosis, signaling, and increases in mechanical stability during cell division, as well as decrease of shear forces during separation of two cells after division, and cell separation from tissues for cancer metastasis. Within the membrane, there are specialized domains, known as lipid rafts. A raft can coordinate various signaling pathways. Recent data on the proteomics of lipid rafts/caveolae have highlighted the enigmatic role of various signaling proteins in cancer development. Analysis of these data of raft proteome from various tumors, cancer tissues, and cell lines cultured without and with therapeutic agents, as well as from model rafts revealed that there may be two subsets of raft assemblage in cell membrane. One subset of raft is enriched with cholesterol-sphingomyeline-ganglioside-cav-1/Src/EGFR (hereafter, "chol-raft") that is involved in normal cell signaling, and when dysregulated promotes cell transformation and tumor progression; another subset of raft is enriched with ceramide-sphingomyeline-ganglioside-FAS/Ezrin (hereafter, "cer-raft") that generally promotes apoptosis. In view of this, and to focus insight into the cancer cell physiology caused by the lipid rafts mediated signals and their receptors, and the downstream transmitters, either proliferative (for example, EGF and EGFR) or death-inducing (for example, FASL and FAS), and the precise roles of some therapeutic drugs and endogenous acid sphingomylenase in this scenario in in situ transformation of "chol-raft" into "cer-raft" are summarized and discussed in this contribution.
Collapse
Affiliation(s)
- Samir Kumar Patra
- Cancer Epigenetics Research, Kalyani (B-7/183), Nadia, West Bengal, India-741235.
| |
Collapse
|