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Liu Y, Luo D, Lu Y, Tan L. E2F transcription factor 1 as a potential prognostic biomarker and promotes tumor proliferation in skin cutaneous melanoma. Pathol Res Pract 2025; 269:155875. [PMID: 40023140 DOI: 10.1016/j.prp.2025.155875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/08/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
Cutaneous melanoma (SKCM) is a highly aggressive malignancy with an overall poor prognosis. The expression of E2F transcription factor 1 in SKCM tissues was analyzed using the data acquired from the Cancer Genome Atlas (TCGA)and Gene Expression Omnibus (GEO)databases. The expression of E2F1 was also analyzed in human biopsies using immunohistology, and its expression was detected in SKCM cell lines using qPCR and WB technology. The prognostic value of E2F transcription factor 1 in SKCM was investigated using Kaplan-Meier survival and Cox analysis. The Tumor Immunization Estimation Resource (TIMER) was used to analyze the invasion of immune cells and associated markers of immune cells. The prognostic value of E2F transcription factor 1 DNA methylation levels for each CpG was analyzed by means of the MethSurv. The results were verified in the Human Protein Atlas (HPA) database. Individuals with elevated E2F transcription factor 1 expression had a worse prognosis (HR=1.43, p = 0.01). Using the expression level of E2F transcription factor 1, a reliable distinction between tumor and normal tissues can be made (Area Under the Curve =0.949). Moreover, immune infiltrations analysis showed that the mRNA expression levels and somatic copy number alterations (SCNA) in E2F transcription factor 1 were significantly correlated with recruitment of several immune cells. Our study showed that overexpression of E2F transcription factor 1 was significantly associated with poor prognosis and malignant phenotype of melanoma cells in SKCM patients.
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Affiliation(s)
- Ying Liu
- Plastic surgery Department, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100038, China
| | - Dan Luo
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Yuangang Lu
- Department of Plastic and Cosmetic Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China. https://twitter.com/
| | - Liuchang Tan
- Department of Plastic and Cosmetic Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China.
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2
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Villoch‐Fernandez J, Martínez‐García N, Martín‐López M, Maeso‐Alonso L, López‐Ferreras L, Vazquez‐Jimenez A, Muñoz‐Hidalgo L, Garcia‐Romero N, Sanchez JM, Fernandez A, Ayuso‐Sacido A, Marques MM, Marin MC. A novel TAp73-inhibitory compound counteracts stemness features of glioblastoma stem cells. Mol Oncol 2025; 19:852-877. [PMID: 39090849 PMCID: PMC11887682 DOI: 10.1002/1878-0261.13694] [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: 12/11/2023] [Revised: 05/01/2024] [Accepted: 06/19/2024] [Indexed: 08/04/2024] Open
Abstract
Glioblastoma (GB) is the most common and fatal type of primary malignant brain tumor for which effective therapeutics are still lacking. GB stem cells, with tumor-initiating and self-renewal capacity, are mostly responsible for GB malignancy, representing a crucial target for therapies. The TP73 gene, which is highly expressed in GB, gives rise to the TAp73 isoform, a pleiotropic protein that regulates neural stem cell biology; however, its role in cancer has been highly controversial. We inactivated TP73 in human GB stem cells and revealed that TAp73 is required for their stemness potential, acting as a regulator of the transcriptional stemness signatures, highlighting TAp73 as a possible therapeutic target. As proof of concept, we identified a novel natural compound with TAp73-inhibitory capacity, which was highly effective against GB stem cells. The treatment reduced GB stem cell-invasion capacity and stem features, at least in part by TAp73 repression. Our data are consistent with a novel paradigm in which hijacking of p73-regulated neurodevelopmental programs, including neural stemness, might sustain tumor progression, pointing out TAp73 as a therapeutic strategy for GB.
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Affiliation(s)
| | | | | | - Laura Maeso‐Alonso
- Instituto de Biomedicina y Departamento de Biología MolecularUniversidad de LeónSpain
| | - Lorena López‐Ferreras
- Instituto de Biomedicina y Departamento de Biología MolecularUniversidad de LeónSpain
| | | | | | - Noemí Garcia‐Romero
- Faculty of Experimental SciencesUniversidad Francisco de VitoriaMadridSpain
- Brain Tumor Laboratory, Fundación VithasGrupo Hospitales VithasMadridSpain
- Faculty of MedicineUniversidad Francisco de VitoriaMadridSpain
| | | | | | - Angel Ayuso‐Sacido
- Faculty of Experimental SciencesUniversidad Francisco de VitoriaMadridSpain
- Brain Tumor Laboratory, Fundación VithasGrupo Hospitales VithasMadridSpain
- Faculty of MedicineUniversidad Francisco de VitoriaMadridSpain
| | - Margarita M. Marques
- Instituto de Desarrollo Ganadero y Sanidad Animal y Departamento de Producción AnimalUniversidad de LeónSpain
| | - Maria C. Marin
- Instituto de Biomedicina y Departamento de Biología MolecularUniversidad de LeónSpain
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3
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Patil MR, Bihari A. Role of artificial intelligence in cancer detection using protein p53: A Review. Mol Biol Rep 2024; 52:46. [PMID: 39658610 DOI: 10.1007/s11033-024-10051-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/22/2024] [Indexed: 12/12/2024]
Abstract
Normal cell development and prevention of tumor formation rely on the tumor-suppressor protein p53. This crucial protein is produced from the Tp53 gene, which encodes the p53 protein. The p53 protein plays a vital role in regulating cell growth, DNA repair, and apoptosis (programmed cell death), thereby maintaining the integrity of the genome and preventing the formation of tumors. Since p53 was discovered 43 years ago, many researchers have clarified its functions in the development of tumors. With the support of the protein p53 and targeted artificial intelligence modeling, it will be possible to detect cancer and tumor activity at an early stage. This will open up new research opportunities. In this review article, a comprehensive analysis was conducted on different machine learning techniques utilized in conjunction with the protein p53 to predict and speculate cancer. The study examined the types of data incorporated and evaluated the performance of these techniques. The aim was to provide a thorough understanding of the effectiveness of machine learning in predicting and speculating cancer using the protein p53.
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Affiliation(s)
- Manisha R Patil
- School of Computer Science Engineering and Information System, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Anand Bihari
- Department of Computational Intelligence, School of Computer Science and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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Nakajima R, Zhou Y, Shirasawa M, Nishimura N, Zhao L, Fikriyanti M, Kamiya Y, Iwanaga R, Bradford AP, Shinmyozu K, Nishibuchi G, Nakayama JI, Kurayoshi K, Araki K, Ohtani K. DEAD/H Box 5 (DDX5) Augments E2F1-Induced Cell Death Independent of the Tumor Suppressor p53. Int J Mol Sci 2024; 25:13251. [PMID: 39769018 PMCID: PMC11675670 DOI: 10.3390/ijms252413251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
In almost all cancers, the p53 pathway is disabled and cancer cells survive. Hence, it is crucially important to induce cell death independent of p53 in the treatment of cancers. The transcription factor E2F1 is controlled by binding of the tumor suppressor pRB, and induces apoptosis by activating the ARF gene, an upstream activator of p53, when deregulated from pRB by loss of pRB function. Deregulated E2F1 can also induce apoptosis, independent of p53, via other targets such as TAp73 and BIM. We searched for novel E2F1-interacting proteins and identified the RNA helicase DEAD/H box 5 (DDX5), which also functions as a transcriptional coactivator. In contrast to the reported growth-promoting roles of DDX5, we show that DDX5 suppresses cell growth and survival by augmentation of deregulated E2F1 activity. Over-expression of DDX5 enhanced E2F1 induction of tumor suppressor gene expression and cell death. Conversely, shRNA-mediated knockdown of DDX5 compromised both. Moreover, DDX5 modulated E2F1-mediated cell death independent of p53, for which DDX5 also functions as a coactivator. Since p53 function is disabled in almost all cancers, these results underscore the roles of DDX5 in E2F1-mediated induction of cell death, independent of p53, and represent novel aspects for the treatment of p53-disabled cancer cells.
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Affiliation(s)
- Rinka Nakajima
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
| | - Yaxuan Zhou
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
| | - Mashiro Shirasawa
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
| | - Naoyasu Nishimura
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
| | - Lin Zhao
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
| | - Mariana Fikriyanti
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
| | - Yuki Kamiya
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
| | - Ritsuko Iwanaga
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Andrew P. Bradford
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Kaori Shinmyozu
- Proteomics Support Unit, RIKEN Center for Developmental Biology, Kobe 650-0047, Hyogo, Japan;
| | - Gohei Nishibuchi
- Laboratory of Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Kyoto, Japan;
| | - Jun-ichi Nakayama
- Division of Chromatin Regulation, National Institute for Basic Biology, Okazaki 444-8585, Aichi, Japan;
- Department of Basic Biology, School of Life Science, The Graduate University for Advanced Studies, SOKENDAI, Okazaki 444-8585, Aichi, Japan
| | - Kenta Kurayoshi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Ishikawa, Japan;
| | - Keigo Araki
- Department of Morphological Biology, Ohu University School of Dentistry, 31-1 Misumido Tomitamachi, Koriyama 963-8611, Fukushima, Japan;
| | - Kiyoshi Ohtani
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (R.N.); (Y.Z.); (M.S.); (N.N.); (L.Z.); (M.F.); (Y.K.)
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Zhang W, Yamamoto K, Chang YH, Yabushita T, Hao Y, Shimura R, Nakahara J, Shikata S, Iida K, Chen Q, Zhang X, Kitamura T, Goyama S. HDAC7 is a potential therapeutic target in acute erythroid leukemia. Leukemia 2024; 38:2614-2627. [PMID: 39277669 PMCID: PMC11588653 DOI: 10.1038/s41375-024-02394-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/17/2024]
Abstract
Acute erythroleukemia (AEL) is a rare subtype of acute myeloid leukemia with a poor prognosis. In this study, we established a novel murine AEL model with Trp53 depletion and ERG overexpression. ERG overexpression in Trp53-deficient mouse bone marrow cells, but not in wild-type bone marrow cells, leads to AEL development within two months after transplantation with 100% penetrance. The established mouse AEL cells expressing Cas9 can be cultured in vitro, induce AEL in vivo even in unirradiated recipient mice, and enable efficient gene ablation using the CRISPR/Cas9 system. We also confirmed the cooperation between ERG overexpression and TP53 inactivation in promoting the growth of immature erythroid cells in human cord blood cells. Mechanistically, ERG antagonizes KLF1 and inhibits erythroid maturation, whereas TP53 deficiency promotes proliferation of erythroid progenitors. Furthermore, we identified HDAC7 as a specific susceptibility in AEL by the DepMap-based two-group comparison analysis. HDAC7 promotes the growth of human and mouse AEL cells both in vitro and in vivo through its non-enzymatic functions. Our study provides experimental evidence that TP53 deficiency and ERG overexpression are necessary and sufficient for the development of AEL and highlights HDAC7 as a promising therapeutic target for this disease.
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Affiliation(s)
- Wenyu Zhang
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Keita Yamamoto
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yu-Hsuan Chang
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
- Division of Molecular Pharmacology of Malignant Diseases, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Tomohiro Yabushita
- Division of Molecular Pharmacology of Malignant Diseases, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yangying Hao
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Ruka Shimura
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Jakushin Nakahara
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Shiori Shikata
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Kohei Iida
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Qianyi Chen
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Xichen Zhang
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Toshio Kitamura
- Division of Molecular Pharmacology of Malignant Diseases, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | - Susumu Goyama
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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6
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López I, Valdivia IL, Vojtesek B, Fåhraeus R, Coates P. Re-appraising the evidence for the source, regulation and function of p53-family isoforms. Nucleic Acids Res 2024; 52:12112-12129. [PMID: 39404067 PMCID: PMC11551734 DOI: 10.1093/nar/gkae855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 11/12/2024] Open
Abstract
The p53 family of proteins evolved from a common ancestor into three separate genes encoding proteins that act as transcription factors with distinct cellular roles. Isoforms of each member that lack specific regions or domains are suggested to result from alternative transcription start sites, alternative splicing or alternative translation initiation, and have the potential to exponentially increase the functional repertoire of each gene. However, evidence supporting the presence of individual protein variants at functional levels is often limited and is inferred by mRNA detection using highly sensitive amplification techniques. We provide a critical appraisal of the current evidence for the origins, expression, functions and regulation of p53-family isoforms. We conclude that despite the wealth of publications, several putative isoforms remain poorly established. Future research with improved technical approaches and the generation of isoform-specific protein detection reagents is required to establish the physiological relevance of p53-family isoforms in health and disease. In addition, our analyses suggest that p53-family variants evolved partly through convergent rather than divergent evolution from the ancestral gene.
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Affiliation(s)
- Ignacio López
- Biochemistry, Faculty of Science, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay
- Cell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay
| | - Irene Larghero Valdivia
- Biochemistry, Faculty of Science, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay
| | - Borivoj Vojtesek
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 65653, Czech Republic
| | - Robin Fåhraeus
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 65653, Czech Republic
- Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris Cité, 27 rue Juliette Dodu, Hôpital St. Louis, Paris F-75010, France
- Department of Medical Biosciences, Building 6M, Umeå University, Umeå 90185, Sweden
| | - Philip J Coates
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 65653, Czech Republic
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7
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Zhao L, Nakajima R, Zhou Y, Shirasawa M, Fikriyanti M, Kamiya Y, Toh H, Komori H, Iwanaga R, Bradford AP, Nishitani H, Kurayoshi K, Araki K, Ohtani K. The N-Terminal Region of the Transcription Factor E2F1 Contains a Novel Transactivation Domain and Recruits General Transcription Factor GTF2H2. Biomolecules 2024; 14:1357. [PMID: 39595534 PMCID: PMC11592155 DOI: 10.3390/biom14111357] [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: 09/13/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
The transcription factor E2F1 is the principal target of the tumor suppressor pRB. E2F1 promotes cell proliferation by activating growth-promoting genes upon growth stimulation. In contrast, E2F1 contributes to tumor suppression by activating tumor suppressor genes, such as ARF, upon loss of pRB function, a major oncogenic change. The transactivation domain of E2F1 has previously been mapped to the C-terminal region. We show here that the N-terminal region of E2F1 is critical for the activation of tumor suppressor genes. Deletion of the N-terminal region dramatically compromised E2F1 activation of tumor suppressor genes. The N-terminal region showed transactivation ability when fused to the DNA-binding domain of GAL4. A search for novel interacting factors with the N-terminal region, using a yeast two-hybrid system, identified the general transcription factor GTF2H2. Overexpression of GTF2H2 enhanced E2F1 activation of tumor suppressor genes and induction of cell death. Conversely, the knockdown of GTF2H2 compromised both. E2F1 binding enhanced the binding of GTF2H2 to target promoters depending on the integrity of the N-terminal region. Taken together, these results suggest that the N-terminal region of E2F1 contains a novel transactivation domain that mediates the activation of tumor suppressor genes, at least in part, by recruiting GTF2H2.
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Affiliation(s)
- Lin Zhao
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
| | - Rinka Nakajima
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
| | - Yaxuan Zhou
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
| | - Mashiro Shirasawa
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
| | - Mariana Fikriyanti
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
| | - Yuki Kamiya
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
| | - Hiroyuki Toh
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
| | - Hideyuki Komori
- Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA;
| | - Ritsuko Iwanaga
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Andrew P. Bradford
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Hideo Nishitani
- Graduate School of Life Science, University of Hyogo, Kamigori, Ako-gun 678-1297, Hyogo, Japan;
| | - Kenta Kurayoshi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Ishikawa, Japan;
| | - Keigo Araki
- Department of Morphological Biology, Ohu University School of Dentistry, 31-1 Misumido Tomitamachi, Koriyama 963-8611, Fukushima, Japan;
| | - Kiyoshi Ohtani
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Hyogo, Japan; (L.Z.); (R.N.); (Y.Z.); (M.S.); (M.F.); (Y.K.); (H.T.)
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8
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Singh S, Gleason CE, Fang M, Laimon YN, Khivansara V, Xie S, Durmaz YT, Sarkar A, Ngo K, Savla V, Li Y, Abu-Remaileh M, Li X, Tuladhar B, Odeh R, Hamkins-Indik F, He D, Membreno MW, Nosrati M, Gushwa NN, Leung SSF, Fraga-Walton B, Hernandez L, Baldomero MP, Lent BM, Spellmeyer D, Luna JF, Hoang D, Gritsenko Y, Chand M, DeMart MK, Metobo S, Bhatt C, Shapiro JA, Yang K, Dupper NJ, Bockus AT, Doench JG, Aggen JB, Liu LF, Levin B, Wang EW, Vendrell I, Fischer R, Kessler B, Gokhale PC, Signoretti S, Spektor A, Kreatsoulas C, Singh R, Earp DJ, Garcia PD, Nijhawan D, Oser MG. Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.01.605889. [PMID: 39211113 PMCID: PMC11360997 DOI: 10.1101/2024.08.01.605889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.
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9
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Panczyszyn E, Saverio V, Monzani R, Gagliardi M, Petrovic J, Stojkovska J, Collavin L, Corazzari M. FSP1 is a predictive biomarker of osteosarcoma cells' susceptibility to ferroptotic cell death and a potential therapeutic target. Cell Death Discov 2024; 10:87. [PMID: 38368399 PMCID: PMC10874395 DOI: 10.1038/s41420-024-01854-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 01/30/2024] [Accepted: 02/06/2024] [Indexed: 02/19/2024] Open
Abstract
Human osteosarcoma (OS) is a relatively rare malignancy preferentially affecting long body bones which prognosis is often poor also due to the lack of effective therapies. Clinical management of this cancer basically relies on surgical removal of primary tumor coupled with radio/chemotherapy. Unfortunately, most osteosarcoma cells are resistant to conventional therapy, with the undergoing epithelial-mesenchymal transition (EMT) giving rise to gene expression reprogramming, thus increasing cancer cell invasiveness and metastatic potential. Alternative clinical approaches are thus urgently needed. In this context, the recently described ferroptotic cell death represents an attractive new strategy to efficiently kill cancer cells, since most chemoresistant and mesenchymal-shaped tumors display high susceptibility to pro-ferroptotic compounds. However, cancer cells have also evolved anti-ferroptotic strategies, which somehow sustain their survival upon ferroptosis induction. Indeed, here we show that osteosarcoma cell lines display heterogeneous sensitivity to ferroptosis execution, correlating with the mesenchymal phenotype, which is consistently affected by the expression of the well-known anti-ferroptotic factor ferroptosis suppressor protein 1 (FSP1). Interestingly, inhibiting the activity or expression of FSP1 restores cancer cell sensitivity to ferroptosis. Moreover, we also found that: i) AKRs might also contribute to resistance; ii) NRF2 enhances FSP1 expression upon ferroptosis induction; while iii) p53 contributes to the regulation of FSP1 basal expression in OS cells.In conclusion, FSP1 expression can potentially be used as a valuable predictive marker of OS sensitivity to ferroptosis and as a new potential therapeutic target.
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Affiliation(s)
- Elzbieta Panczyszyn
- Department of Health Sciences and Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Valentina Saverio
- Department of Health Sciences and Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Romina Monzani
- Department of Health Sciences and Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Mara Gagliardi
- Department of Health Sciences and Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
- Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy
| | - Jelena Petrovic
- University of Belgrade, Faculty of Technology and Metallurgy, Belgrade, Serbia
- Innovation Center of the Faculty of Technology and Metallurgy, Belgrade, Serbia
| | - Jasmina Stojkovska
- University of Belgrade, Faculty of Technology and Metallurgy, Belgrade, Serbia
| | - Licio Collavin
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Marco Corazzari
- Department of Health Sciences and Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy.
- Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy.
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10
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Chen J, Laverty DJ, Talele S, Bale A, Carlson BL, Porath KA, Bakken KK, Burgenske DM, Decker PA, Vaubel RA, Eckel-Passow JE, Bhargava R, Lou Z, Hamerlik P, Harley B, Elmquist WF, Nagel ZD, Gupta SK, Sarkaria JN. Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization. Sci Transl Med 2024; 16:eadj5962. [PMID: 38354228 PMCID: PMC11064970 DOI: 10.1126/scitranslmed.adj5962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024]
Abstract
ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0-G1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53-mutant tumors but not in TP53-WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53-mutant, but not in TP53-WT, PDXs. In plasmid-based reporter assays, GBM43 (TP53-mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.
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Affiliation(s)
- Jiajia Chen
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Daniel J. Laverty
- Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
| | - Surabhi Talele
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55905, USA
| | - Ashwin Bale
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Brett L. Carlson
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Kendra A. Porath
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Katrina K. Bakken
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Paul A. Decker
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Rachael A. Vaubel
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Rohit Bhargava
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Zhenkun Lou
- Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Brendan Harley
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - William F. Elmquist
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55905, USA
| | - Zachary D. Nagel
- Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
| | - Shiv K. Gupta
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jann N. Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
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11
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Zhou Y, Nakajima R, Shirasawa M, Fikriyanti M, Zhao L, Iwanaga R, Bradford AP, Kurayoshi K, Araki K, Ohtani K. Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression. BIOLOGY 2023; 12:1511. [PMID: 38132337 PMCID: PMC10740672 DOI: 10.3390/biology12121511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology.
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Affiliation(s)
- Yaxuan Zhou
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Rinka Nakajima
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Mashiro Shirasawa
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Mariana Fikriyanti
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Lin Zhao
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
| | - Ritsuko Iwanaga
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Andrew P. Bradford
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045, USA; (R.I.); (A.P.B.)
| | - Kenta Kurayoshi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan;
| | - Keigo Araki
- Department of Morphological Biology, Ohu University School of Dentistry, 31-1 Misumido Tomitamachi, Koriyama, Fukushima 963-8611, Japan;
| | - Kiyoshi Ohtani
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo 669-1330, Japan; (Y.Z.); (R.N.); (M.S.); (M.F.); (L.Z.)
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12
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Takeuchi H, Koga M, Doi K, Sakurai H. PP2A and its adapter protein IER5 induce the DNA-binding ability and target gene expression of E2F1 via dephosphorylation at serine 375. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194960. [PMID: 37467925 DOI: 10.1016/j.bbagrm.2023.194960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/12/2023] [Accepted: 07/15/2023] [Indexed: 07/21/2023]
Abstract
The transcription factor E2F1 participates in cell cycle control through transcriptional activation of genes that promote S-phase entry. E2F1 is also linked to the expression of proapoptotic genes, and the loss of E2F1 activity facilitates tumor progression by reducing cellular apoptosis. Phosphorylation controlled by protein kinases and phosphatases is the major posttranslational modification and regulates the cellular levels and transactivator function of E2F1. Here, we characterize the regulatory roles of serine-375 (S375), one of the major phosphorylation sites of E2F1. Cyclin-dependent kinases such as CDK8 phosphorylate at S375 of E2F1, which is dephosphorylated by protein phosphatase 2A (PP2A) containing the B55 regulatory subunit. The PP2A adapter protein IER5 binds to both PP2A/B55 and E2F1 and assists dephosphorylation at S375 by PP2A. S375-dephosphorylated E2F1 exhibits higher DNA-binding affinity than the phosphorylated form. Although the promoter regions of proapoptotic genes are less occupied by E2F1 in cells, an increase in S375-dephosphorylated E2F1 induces preferential binding of E2F1 to the proapoptotic gene promoters and their expression. Our data identify PP2A/B55-IER5 as a critical regulator of E2F1 and suggest that the phosphorylation state of E2F1 is an important determinant for the expression of proapoptotic genes.
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Affiliation(s)
- Hiroto Takeuchi
- Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942, Japan
| | - Mayuko Koga
- Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942, Japan
| | - Kuriko Doi
- Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942, Japan
| | - Hiroshi Sakurai
- Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942, Japan.
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13
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Wang Y, Chen L, Wang L, Pei G, Cheng H, Zhang Q, Wang S, Hu D, He Y, He C, Fu C, Wei Q. Pulsed Electromagnetic Fields Combined With Adipose-Derived Stem Cells Protect Ischemic Myocardium by Regulating miR-20a-5p/E2F1/p73 Signaling. Stem Cells 2023; 41:724-737. [PMID: 37207995 DOI: 10.1093/stmcls/sxad037] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 05/03/2023] [Indexed: 05/21/2023]
Abstract
Myocardial infarction (MI) is a serious threat to human health. Although monotherapy with pulsed electromagnetic fields (PEMFs) or adipose-derived stem cells (ADSCs) has been reported to have positive effect on the treatment of MI, a satisfactory outcome has not yet been achieved. In recent years, combination therapy has attracted widespread interest. Herein, we explored the synergistic therapeutic effect of combination therapy with PEMFs and ADSCs on MI and found that the combination of PEMFs and ADSCs effectively reduced infarct size, inhibited cardiomyocyte apoptosis and protected the cardiac function in mice with MI. In addition, bioinformatics analysis and RT-qPCR showed that the combination therapy could affect apoptosis by regulating the expression of miR-20a-5p. A dual-luciferase reporter gene assay also confirmed that the miR-20a-5p could target E2F transcription factor 1 (E2F1) and inhibit cardiomyocyte apoptosis by regulating the E2F1/p73 signaling pathway. Therefore, our study systematically demonstrated the effectiveness of combination therapy on the inhibition of cardiomyocyte apoptosis by regulating the miR-20a-5p/E2F1/p73 signaling pathway in mice with MI. Thus, our study underscored the effectiveness of the combination of PEMFs and ADSCs and identified miR-20a-5p as a promising therapeutic target for the treatment of MI in the future.
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Affiliation(s)
- Yang Wang
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Li Chen
- Department of Rehabilitation Medicine, The Fifth Affiliated People's Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Lu Wang
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Gaiqin Pei
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Hongxin Cheng
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Qing Zhang
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Shiqi Wang
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Danrong Hu
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Yong He
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Chengqi He
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
| | - Chenying Fu
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Aging and Geriatric Mechanism Laboratory, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Quan Wei
- Department of Rehabilitation Medicine and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, People's Republic of China
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14
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Burlibasa L, Nicu AT, Chifiriuc MC, Medar C, Petrescu A, Jinga V, Stoica I. H3 histone methylation landscape in male urogenital cancers: from molecular mechanisms to epigenetic biomarkers and therapeutic targets. Front Cell Dev Biol 2023; 11:1181764. [PMID: 37228649 PMCID: PMC10203431 DOI: 10.3389/fcell.2023.1181764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
During the last decades, male urogenital cancers (including prostate, renal, bladder and testicular cancers) have become one of the most frequently encountered malignancies affecting all ages. While their great variety has promoted the development of various diagnosis, treatment and monitoring strategies, some aspects such as the common involvement of epigenetic mechanisms are still not elucidated. Epigenetic processes have come into the spotlight in the past years as important players in the initiation and progression of tumors, leading to a plethora of studies highlighting their potential as biomarkers for diagnosis, staging, prognosis, and even as therapeutic targets. Thus, fostering research on the various epigenetic mechanisms and their roles in cancer remains a priority for the scientific community. This review focuses on one of the main epigenetic mechanisms, namely, the methylation of the histone H3 at various sites and its involvement in male urogenital cancers. This histone modification presents a great interest due to its modulatory effect on gene expression, leading either to activation (e.g., H3K4me3, H3K36me3) or repression (e.g., H3K27me3, H3K9me3). In the last few years, growing evidence has demonstrated the aberrant expression of enzymes that methylate/demethylate histone H3 in cancer and inflammatory diseases, that might contribute to the initiation and progression of such disorders. We highlight how these particular epigenetic modifications are emerging as potential diagnostic and prognostic biomarkers or targets for the treatment of urogenital cancers.
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Affiliation(s)
| | | | - Mariana Carmen Chifiriuc
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Academy of Romanian Scientists, Bucharest, Romania
- Romanian Academy, Bucharest, Romania
| | - Cosmin Medar
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Amelia Petrescu
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Viorel Jinga
- Academy of Romanian Scientists, Bucharest, Romania
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
- Clinical Hospital “Prof. dr Theodor Burghele”, Bucharest, Romania
| | - Ileana Stoica
- Faculty of Biology, University of Bucharest, Bucharest, Romania
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15
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Nakajima R, Deguchi R, Komori H, Zhao L, Zhou Y, Shirasawa M, Angelina A, Goto Y, Tohjo F, Nakahashi K, Nakata K, Iwanaga R, Bradford AP, Araki K, Warita T, Ohtani K. The TFDP1 gene coding for DP1, the heterodimeric partner of the transcription factor E2F, is a target of deregulated E2F. Biochem Biophys Res Commun 2023; 663:154-162. [PMID: 37141667 DOI: 10.1016/j.bbrc.2023.04.092] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/06/2023]
Abstract
The TFDP1 gene codes for the heterodimeric partner DP1 of the transcription factor E2F. E2F, principal target of the tumor suppressor pRB, plays central roles in cell proliferation by activating a group of growth-related genes. E2F also mediates tumor suppression by activating tumor suppressor genes such as ARF, an upstream activator of the tumor suppressor p53, when deregulated from pRB upon oncogenic changes. Among 8 E2F family members (E2F1∼E2F8), expression of activator E2Fs (E2F1∼E2F3a) is induced at the G1/S boundary of the cell cycle after growth stimulation by E2F itself. However, mechanisms regulating DP1 expression are not known. We show here that over-expression of E2F1 and forced inactivation of pRB, by adenovirus E1a, induced TFDP1 gene expression in human normal fibroblast HFFs, suggesting that the TFDP1 gene is a target of E2F. Serum stimulation of HFFs also induced TFDP1 gene expression, but with different kinetics from that of the CDC6 gene, a typical growth-related E2F target. Both over-expression of E2F1 and serum stimulation activated the TFDP1 promoter. We searched for E2F1-responsive regions by 5' and 3' deletion of the TFDP1 promoter and by introducing point mutations in putative E2F1-responsive elements. Promoter analysis identified several GC-rich elements, mutation of which reduced E2F1-responsiveness but not serum-responsiveness. ChIP assays showed that the GC-rich elements bound deregulated E2F1 but not physiological E2F1 induced by serum stimulation. These results suggest that the TFDP1 gene is a target of deregulated E2F. In addition, knockdown of DP1 expression by shRNA enhanced ARF gene expression, which is specifically induced by deregulated E2F activity, suggesting that activation of the TFDP1 gene by deregulated E2F may function as a failsafe feedback mechanism to suppress deregulated E2F and maintain normal cell growth in the event that DP1 expression is insufficient relative to that of its partner activator E2Fs. a maximum of 6 keywords: E2F, DP1, TFDP1 gene, pRB, gene expression.
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Affiliation(s)
- Rinka Nakajima
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Reika Deguchi
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Hideyuki Komori
- Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI, 48109-2216, USA
| | - Lin Zhao
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Yaxuan Zhou
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Mashiro Shirasawa
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Arlene Angelina
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Yasuko Goto
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Fumiya Tohjo
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Kengo Nakahashi
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Kimi Nakata
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Ritsuko Iwanaga
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO, 80045, USA
| | - Andrew P Bradford
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO, 80045, USA
| | - Keigo Araki
- Department of Morphological Biology, Ohu University School of Dentistry, 31-1 Misumido Tomitamachi, Koriyama, Fukushima, 963-8611, Japan
| | - Tomoko Warita
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan
| | - Kiyoshi Ohtani
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1337, Japan.
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16
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Deregulated E2F Activity as a Cancer-Cell Specific Therapeutic Tool. Genes (Basel) 2023; 14:genes14020393. [PMID: 36833320 PMCID: PMC9956157 DOI: 10.3390/genes14020393] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/24/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
The transcription factor E2F, the principal target of the tumor suppressor pRB, plays crucial roles in cell proliferation and tumor suppression. In almost all cancers, pRB function is disabled, and E2F activity is enhanced. To specifically target cancer cells, trials have been undertaken to suppress enhanced E2F activity to restrain cell proliferation or selectively kill cancer cells, utilizing enhanced E2F activity. However, these approaches may also impact normal growing cells, since growth stimulation also inactivates pRB and enhances E2F activity. E2F activated upon the loss of pRB control (deregulated E2F) activates tumor suppressor genes, which are not activated by E2F induced by growth stimulation, inducing cellular senescence or apoptosis to protect cells from tumorigenesis. Deregulated E2F activity is tolerated in cancer cells due to inactivation of the ARF-p53 pathway, thus representing a feature unique to cancer cells. Deregulated E2F activity, which activates tumor suppressor genes, is distinct from enhanced E2F activity, which activates growth-related genes, in that deregulated E2F activity does not depend on the heterodimeric partner DP. Indeed, the ARF promoter, which is specifically activated by deregulated E2F, showed higher cancer-cell specific activity, compared to the E2F1 promoter, which is also activated by E2F induced by growth stimulation. Thus, deregulated E2F activity is an attractive potential therapeutic tool to specifically target cancer cells.
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Han Z, Wang L, Wang D, Zhang L, Bi Y, Zheng X, Liu W, Bai G, Wang Z, Wan W, Ma Y, Cai X, Liu T, Jia Q. DJ-1 promotes osteosarcoma progression through activating CDK4/RB/E2F1 signaling pathway. Front Oncol 2022; 12:1036401. [PMID: 36408174 PMCID: PMC9671360 DOI: 10.3389/fonc.2022.1036401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/17/2022] [Indexed: 11/07/2023] Open
Abstract
Osteosarcoma (OS) is a primary malignant tumor of the bone characterized by poor prognosis due to chemotherapy resistance and high recurrence rates. DJ-1 (PARK7) is known as an oncogene and its abnormal expression is related to the poor prognosis of various types of malignant tumors. It was found in this study that upregulated expression of DJ-1 was closely correlated with the prognosis of OS patients by promoting the proliferation, migration and chemotherapy resistance of OS cells in vitro through regulating the activity of CDK4 but not through the oxidation mechanism or AKT pathway. The combination of DJ-1 and CDK4 promoted RB phosphorylation, leading to the dissociation of E2F1 into the nucleus to regulate the expression of cell cycle-related genes. The tumor xenograft mouse model demonstrated that DJ-1 knockout suppressed tumor growth in vivo. All these findings indicate that DJ-1 can affect the occurrence and progression of OS by regulating the CDK/RB/E2F1axis, suggesting a novel therapeutic opportunity for OS patients.
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Affiliation(s)
- Zhitao Han
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lining Wang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dongshuo Wang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Luosheng Zhang
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yifeng Bi
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xinlei Zheng
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Weibo Liu
- Department of Orthopaedics, the Fourth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Guangjian Bai
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhenhua Wang
- Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Wei Wan
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yong Ma
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xiaopan Cai
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Tielong Liu
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Qi Jia
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
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18
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Adan H, Guy S, Arulanandam R, Geletu M, Daniel J, Raptis L. Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts. Cancer Gene Ther 2022; 29:1502-1513. [PMID: 35411090 PMCID: PMC9576600 DOI: 10.1038/s41417-022-00462-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/08/2022] [Accepted: 03/18/2022] [Indexed: 01/05/2023]
Abstract
We previously demonstrated that engagement of cadherins, cell to cell adhesion molecules, triggers a dramatic increase in levels and activity of the Rac/Cdc42 small GTPases, which is followed by secretion of IL6 family cytokines and activation of their common receptor, gp130, in an autocrine manner. This results in phosphorylation of the Signal Transducer and Activator of Transcription-3 (Stat3) on tyrosine-705, which then dimerizes, migrates to the nucleus, and activates transcription of genes involved in cell division and survival. In the present report we demonstrate that, in mouse Balb/c3T3 fibroblasts, mutationally activated Src527F also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers the Stat3-ptyr705 increase. Interestingly, our results also demonstrate that cadherin-11 is required to preserve gp130 levels for IL6 family signaling. At the same time, however, activated Src527F downregulates cadherin-11, in a quantitative manner. As a result, Src527F expression to intermediate levels allows sufficient cadherin-11, hence gp130 levels for Stat3 activation, as expected. However, expressed to high levels, Src527F eliminates cadherin-11, hence gp130 signaling, thus abolishing Stat3-ptyr705 stimulation. Taken together, these data establish for the first time a loop between Src, cadherin-11, gp130, and Stat3 activation. This fine balance between Src527F and cadherin-11 levels which is required for Stat3 activation and cellular survival could have significant therapeutic implications.
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Affiliation(s)
- Hanad Adan
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada
- Department of Biology, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Stephanie Guy
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, K1N 6N5, Canada
| | - Rozanne Arulanandam
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, K1N 6N5, Canada
| | - Mulu Geletu
- Department of Chemistry, University of Toronto, Mississauga, ON, L5L 1C6, Canada
| | - Juliet Daniel
- Department of Biology, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Leda Raptis
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, K7L 3N6, Canada.
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Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats. Cell Death Dis 2022; 13:716. [PMID: 35977948 PMCID: PMC9385859 DOI: 10.1038/s41419-022-05160-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 01/21/2023]
Abstract
The tumor suppressor p53 is thought to play a key role in the maintenance of cell size and homeostasis, but relatively little is known about its role in skeletal muscle. Based on its ability to suppress cell growth, we hypothesized that inhibiting the function of wild-type p53 through the overexpression of a dominant-negative p53 mutant (DDp53) could result in muscle fiber hypertrophy. To test this hypothesis, we electroporated adult rat tibialis anterior muscles with DDp53 and collected the tissue three weeks later. We confirmed successful overexpression of DDp53 on a histological and biochemical level and found pronounced changes to muscle architecture, metabolism, and molecular signaling. Muscle mass, fiber cross-sectional area, and fiber diameter significantly decreased with DDp53 overexpression. We found histopathological changes in DDp53 transfected muscle which were accompanied by increased levels of proteins that are associated with membrane damage and repair. In addition, DDp53 decreased oxidative phosphorylation complex I and V protein levels, and despite its negative effects on muscle mass and fiber size, caused an increase in muscle protein synthesis as assessed via the SUnSET technique. Interestingly, the increase in muscle protein synthesis was concomitant with a decrease in phospho-S6K1 (Thr389). Furthermore, the muscle wasting in the DDp53 electroporated leg was accompanied by a decrease in global protein ubiquitination and an increase in proteasome activity. In conclusion, overexpression of a dominant-negative p53 mutant in skeletal muscle results in decreased muscle mass, myofiber size, histological muscle damage, a metabolic phenotype, and perturbed homeostasis between muscle protein synthesis and degradation.
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20
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Roads to Stat3 Paved with Cadherins. Cells 2022; 11:cells11162537. [PMID: 36010614 PMCID: PMC9406956 DOI: 10.3390/cells11162537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/01/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
The engagement of cadherins, cell-to-cell adhesion proteins, triggers a dramatic increase in the levels and activity of the Rac/Cdc42 GTPases, through the inhibition of proteasomal degradation. This leads to an increase in transcription and secretion of IL6 family cytokines, activation of their common receptor, gp130, in an autocrine manner and phosphorylation of the signal transducer and activator of transcription-3 (Stat3) on tyrosine-705 by the Jak kinases. Stat3 subsequently dimerizes, migrates to the nucleus and activates the transcription of genes involved in cell division and survival. The Src oncogene also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers a Stat3-ptyr705 increase. Interestingly, at the same time, Src downregulates cadherins in a quantitative manner, while cadherins are required to preserve gp130 levels for IL6 family signalling. Therefore, a fine balance between Src527F/Rac/IL6 and Src527F/cadherin/gp130 levels is in existence, which is required for Stat3 activation. This further demonstrates the important role of cadherins in the activation of Stat3, through preservation of gp130 function. Conversely, the absence of cadherin engagement correlates with low Stat3 activity: In sparsely growing cells, both gp130 and Stat3-ptyr705 levels are very low, despite the fact that cSrc is active in the FAK (focal adhesion kinase)/cSrc complex, which further indicates that the engagement of cadherins is important for Stat3 activation, not just their presence. Furthermore, the caveolin-1 protein downregulates Stat3 through binding and sequestration of cadherins to the scaffolding domain of caveolin-1. We hypothesize that the cadherins/Rac/gp130 axis may be a conserved pathway to Stat3 activation in a number of systems. This fact could have significant implications in Stat3 biology, as well as in drug testing and development.
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21
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Zhang Y, Xu Y, Lu W, Li J, Yu S, Brown EJ, Stanger BZ, Rabinowitz JD, Yang X. G6PD-mediated increase in de novo NADP + biosynthesis promotes antioxidant defense and tumor metastasis. SCIENCE ADVANCES 2022; 8:eabo0404. [PMID: 35857842 PMCID: PMC9299539 DOI: 10.1126/sciadv.abo0404] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 06/03/2022] [Indexed: 05/11/2023]
Abstract
Metastasizing cancer cells are able to withstand high levels of oxidative stress through mechanisms that are poorly understood. Here, we show that under various oxidative stress conditions, pancreatic cancer cells markedly expand NADPH and NADP+ pools. This expansion is due to up-regulation of glucose-6-phosphate dehydrogenase (G6PD), which stimulates the cytoplasmic nicotinamide adenine dinucleotide kinase (NADK1) to produce NADP+ while converting NADP+ to NADPH. G6PD is activated by the transcription factor TAp73, which is, in turn, regulated by two pathways. Nuclear factor-erythroid 2 p45-related factor-2 suppresses expression of the ubiquitin ligase PIRH2, stabilizing the TAp73 protein. Checkpoint kinases 1/2 and E2F1 induce expression of the TAp73 gene. Levels of G6PD and its upstream activators are elevated in metastatic pancreatic cancer. Knocking down G6PD impedes pancreatic cancer metastasis, whereas forced G6PD expression promotes it. These findings reveal an intracellular network that maintains redox homeostasis through G6PD-mediated increase in de novo NADP+ biosynthesis, which may be co-opted by tumor cells to enable metastasis.
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Affiliation(s)
- Yang Zhang
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yi Xu
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Wenyun Lu
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA
- Department of Chemistry, Princeton University, Princeton, NJ 08540, USA
| | - Jinyang Li
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sixiang Yu
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eric J. Brown
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ben Z. Stanger
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joshua D. Rabinowitz
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA
- Department of Chemistry, Princeton University, Princeton, NJ 08540, USA
| | - Xiaolu Yang
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
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22
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Context-dependent activation of p53 target genes and induction of apoptosis by actinomycin D in aerodigestive tract cancers. Apoptosis 2022; 27:342-353. [PMID: 35267106 DOI: 10.1007/s10495-022-01720-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2022] [Indexed: 01/09/2023]
Abstract
Actinomycin D (ActD) was the first anticancer antibiotic approved for the management of human cancers. However, the notorious toxicity profile limits its widespread application in cancers, including cancers of the aerodigestive tract. Recent studies show that combining low-dose ActD with existing chemotherapies could potentially protect normal cells from the toxicity of chemotherapy drugs through p53 activation (cyclotherapy). An understanding of ActD's effect on p53 signaling is critical for the meaningful application of ActD in cyclotherapy-based combinations. This study evaluated the anti-tumor efficacy and mechanism of action of ActD in aerodigestive tract cancers. We found that ActD strongly inhibited the growth of a panel of aerodigestive tract cancer cell lines and induced efficient apoptosis, although the sensitivity varies among cell lines. The IC50 values of ActD spanned between 0.021 and 2.96 nM. Mechanistic studies revealed that ActD increased the expression of total and phosphorylated p53 (ser15) in a time- and dose-dependent manner. Moreover, ActD-induced apoptosis is dependent on p53 in cells expressing wild-type p53 and that ActD induced context-dependent differential expression of downstream targets p21 and PUMA without significant effects on p27. In the final analysis, this study revealed that p53-p21 is the predominant pathway activated by low-dose ActD, supporting further development of ActD in cyclotherapy.
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23
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Marei HE, Althani A, Afifi N, Hasan A, Caceci T, Pozzoli G, Morrione A, Giordano A, Cenciarelli C. p53 signaling in cancer progression and therapy. Cancer Cell Int 2021; 21:703. [PMID: 34952583 PMCID: PMC8709944 DOI: 10.1186/s12935-021-02396-8] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 12/06/2021] [Indexed: 12/21/2022] Open
Abstract
The p53 protein is a transcription factor known as the "guardian of the genome" because of its critical function in preserving genomic integrity. The TP53 gene is mutated in approximately half of all human malignancies, including those of the breast, colon, lung, liver, prostate, bladder, and skin. When DNA damage occurs, the TP53 gene on human chromosome 17 stops the cell cycle. If p53 protein is mutated, the cell cycle is unrestricted and the damaged DNA is replicated, resulting in uncontrolled cell proliferation and cancer tumours. Tumor-associated p53 mutations are usually associated with phenotypes distinct from those caused by the loss of the tumor-suppressing function exerted by wild-type p53protein. Many of these mutant p53 proteins have oncogenic characteristics, and therefore modulate the ability of cancer cells to proliferate, escape apoptosis, invade and metastasize. Because p53 deficiency is so common in human cancer, this protein is an excellent option for cancer treatment. In this review, we will discuss some of the molecular pathways by which mutant p53 proteins might perform their oncogenic activities, as well as prospective treatment methods based on restoring tumor suppressive p53 functions.
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Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35116, Egypt.
| | - Asmaa Althani
- Biomedical Research Center, Qatar University, Doha, Qatar
| | | | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| | - Thomas Caceci
- Biomedical Sciences, Virginia Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Giacomo Pozzoli
- Pharmacology Unit, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
| | - Andrea Morrione
- Sbarro Institute for Cancer Research and Molecular Medicine. Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine. Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
- Department of Medical Biotechnology, University of Siena, Siena, Italy
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24
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Huang J, Wang Y, Liu J, Chu M, Wang Y. TFDP3 as E2F Unique Partner, Has Crucial Roles in Cancer Cells and Testis. Front Oncol 2021; 11:742462. [PMID: 34745961 PMCID: PMC8564135 DOI: 10.3389/fonc.2021.742462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/30/2021] [Indexed: 12/03/2022] Open
Abstract
Transcription factor DP family member 3 (TFDP3) is a cancer-testis antigen, mainly expressed in normal testis and multiple cancers. TFDP3 gene (Gene ID: 51270) is located on the chromosome X and shares a high degree of sequence homology with TFDP1 and TFDP2, which can form heterodimers with E2F family members and enhance DNA-binding activity of E2Fs. In contrast to TFDP1 and TFDP2, TFDP3 downregulates E2F-mediated transcriptional activation. During DNA damage response in cancer cells, TFDP3 is induced and can inhibit E2F1-mediated apoptosis. Moreover, TFDP3 is involved in cell autophagy and epithelial-mesenchymal transition. Regarding cancer therapy opportunity, the transduction of dendritic cells with recombinant adenovirus-encoding TFDP3 can activate autologous cytotoxic T lymphocytes to target hepatoma cells. Here, we review the characterization of TFDP3, with an emphasis on the biological function and molecular mechanism. A better understanding of TFDP3 will provide new insights into the pathological mechanisms and therapeutic strategies for cancers.
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Affiliation(s)
- Jiahao Huang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
| | - Yini Wang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
| | - Jinlong Liu
- Department of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Ming Chu
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
| | - Yuedan Wang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
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25
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Rozenberg JM, Zvereva S, Dalina A, Blatov I, Zubarev I, Luppov D, Bessmertnyi A, Romanishin A, Alsoulaiman L, Kumeiko V, Kagansky A, Melino G, Ganini C, Barlev NA. The p53 family member p73 in the regulation of cell stress response. Biol Direct 2021; 16:23. [PMID: 34749806 PMCID: PMC8577020 DOI: 10.1186/s13062-021-00307-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/12/2021] [Indexed: 12/14/2022] Open
Abstract
During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeostasis and resulting in subsequent hyperplasia. This process is paralleled by resumption of cell cycle, aberrant DNA repair and blunting the apoptotic program in response to DNA damage. In most human cancers these processes are associated with malfunctioning of tumor suppressor p53. Intriguingly, in some cases two other members of the p53 family of proteins, transcription factors p63 and p73, can compensate for loss of p53. Although both p63 and p73 can bind the same DNA sequences as p53 and their transcriptionally active isoforms are able to regulate the expression of p53-dependent genes, the strongest overlap with p53 functions was detected for p73. Surprisingly, unlike p53, the p73 is rarely lost or mutated in cancers. On the contrary, its inactive isoforms are often overexpressed in cancer. In this review, we discuss several lines of evidence that cancer cells develop various mechanisms to repress p73-mediated cell death. Moreover, p73 isoforms may promote cancer growth by enhancing an anti-oxidative response, the Warburg effect and by repressing senescence. Thus, we speculate that the role of p73 in tumorigenesis can be ambivalent and hence, requires new therapeutic strategies that would specifically repress the oncogenic functions of p73, while keeping its tumor suppressive properties intact.
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Affiliation(s)
- Julian M Rozenberg
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
| | - Svetlana Zvereva
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Aleksandra Dalina
- The Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow, Russia
| | - Igor Blatov
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Ilya Zubarev
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Daniil Luppov
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | | | - Alexander Romanishin
- School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.,School of Life Sciences, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Lamak Alsoulaiman
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Vadim Kumeiko
- School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
| | - Alexander Kagansky
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.,School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
| | - Gerry Melino
- Department of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Ganini
- Department of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Nikolai A Barlev
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia. .,Institute of Cytology, Russian Academy of Science, Saint-Petersburg, Russia.
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26
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MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53. Proc Natl Acad Sci U S A 2021; 118:2102420118. [PMID: 34716260 DOI: 10.1073/pnas.2102420118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 09/21/2021] [Indexed: 02/08/2023] Open
Abstract
The p53 tumor suppressor protein, known to be critically important in several processes including cell-cycle arrest and apoptosis, is highly regulated by multiple mechanisms, most certifiably the Murine Double Minute 2-Murine Double Minute X (MDM2-MDMX) heterodimer. The role of MDM2-MDMX in cell-cycle regulation through inhibition of p53 has been well established. Here we report that in cells either lacking p53 or expressing certain tumor-derived mutant forms of p53, loss of endogenous MDM2 or MDMX, or inhibition of E3 ligase activity of the heterocomplex, causes cell-cycle arrest. This arrest is correlated with a reduction in E2F1, E2F3, and p73 levels. Remarkably, direct ablation of endogenous p73 produces a similar effect on the cell cycle and the expression of certain E2F family members at both protein and messenger RNA levels. These data suggest that MDM2 and MDMX, working at least in part as a heterocomplex, may play a p53-independent role in maintaining cell-cycle progression by promoting the activity of E2F family members as well as p73, making them a potential target of interest in cancers lacking wild-type p53.
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27
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Noor H, Briggs NE, McDonald KL, Holst J, Vittorio O. TP53 Mutation Is a Prognostic Factor in Lower Grade Glioma and May Influence Chemotherapy Efficacy. Cancers (Basel) 2021; 13:5362. [PMID: 34771529 PMCID: PMC8582451 DOI: 10.3390/cancers13215362] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/17/2021] [Accepted: 10/22/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Identification of prognostic biomarkers in cancers is a crucial step to improve overall survival (OS). Although mutations in tumour protein 53 (TP53) is prevalent in astrocytoma, the prognostic effects of TP53 mutation are unclear. METHODS In this retrospective study, we sequenced TP53 exons 1 to 10 in a cohort of 102 lower-grade glioma (LGG) subtypes and determined the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. Publicly available datasets were analysed to confirm the findings. RESULTS In astrocytoma, mutations in TP53 codon 273 were associated with a significantly increased OS compared to the TP53 wild-type (HR (95% CI): 0.169 (0.036-0.766), p = 0.021). Public datasets confirmed these findings. TP53 codon 273 mutant astrocytomas were significantly more chemosensitive than TP53 wild-type astrocytomas (HR (95% CI): 0.344 (0.13-0.88), p = 0.0148). Post-chemotherapy, a significant correlation between TP53 and YAP1 mRNA was found (p = 0.01). In O (6)-methylguanine methyltransferase (MGMT) unmethylated chemotherapy-treated astrocytoma, both TP53 codon 273 and YAP1 mRNA were significant prognostic markers. In oligodendroglioma, TP53 mutations were associated with significantly decreased OS. CONCLUSIONS Based on these findings, we propose that certain TP53 mutant astrocytomas are chemosensitive through the involvement of YAP1, and we outline a potential mechanism. Thus, TP53 mutations may be key drivers of astrocytoma therapeutic efficacy and influence survival outcomes.
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Affiliation(s)
- Humaira Noor
- Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2031, Australia;
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia;
| | - Nancy E. Briggs
- Stats Central, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW 2031, Australia;
| | - Kerrie L. McDonald
- Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2031, Australia;
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia;
| | - Jeff Holst
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia;
- Translational Cancer Metabolism Laboratory, School of Medical Sciences, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2031, Australia
| | - Orazio Vittorio
- School of Women’s & Children’s Health, UNSW Medicine, University of NSW, Randwick, NSW 2031, Australia;
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW 2031, Australia
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Zhang H, Bian C, Tu S, Yin F, Guo P, Zhang J, Song X, Liu Q, Chen C, Han Y. Integrated analysis of lncRNA-miRNA-mRNA ceRNA network in human aortic dissection. BMC Genomics 2021; 22:724. [PMID: 34620091 PMCID: PMC8495997 DOI: 10.1186/s12864-021-08012-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/13/2021] [Indexed: 12/14/2022] Open
Abstract
Background Many studies on long chain non-coding RNAs (lncRNAs) are published in recent years. But the roles of lncRNAs in aortic dissection (AD) are still unclear and should be further examined. The present work focused on determining the molecular mechanisms underlying lncRNAs regulation in aortic dissection on the basis of the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network. Methods This study collected the lncRNAs (GSE52093), mRNAs (GSE52093) and miRNAs (GSE92427) expression data within human tissue samples with aortic dissection group and normal group based on Gene Expression Omnibus (GEO) database. Results This study identified three differentially expressed lncRNAs (DELs), 19 differentially expressed miRNAs (DEmiRs) and 1046 differentially expressed mRNAs (DEGs) identified regarding aortic dissection. Furthermore, we constructed a lncRNA-miRNA-mRNA network through three lncRNAs (including two with up-regulation and one with down-regulation), five miRNAs (five with up-regulation), as well as 211 mRNAs (including 103 with up-regulation and 108 with down-regulation). Simultaneously, we conducted functional enrichment and pathway analyses on genes within the as-constructed ceRNA network. According to our PPI/ceRNA network and functional enrichment analysis results, four critical genes were found (E2F2, IGF1R, BDNF and PPP2R1B). In addition, E2F2 level was possibly modulated via lncRNA FAM87A-hsa-miR-31-5p/hsa-miR-7-5p or lncRNA C9orf106-hsa-miR-7-5p. The expression of IGF1R may be regulated by lncRNA FAM87A-hsa-miR-16-5p/hsa-miR-7-5p or lncRNA C9orf106-hsa-miR-7-5p. Conclusion In conclusion, the ceRNA interaction axis we identified is a potentially critical target for treating AD. Our results shed more lights on the possible pathogenic mechanism in AD using a lncRNA-associated ceRNA network.
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Affiliation(s)
- Hao Zhang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian, China
| | - Ce Bian
- Department of Cardiovascular Surgery, The General Hospital of the PLA Rocket Force, Beijing Normal University, Beijing, China
| | - Simei Tu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian, China
| | - Fanxing Yin
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian, China
| | - Panpan Guo
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian, China
| | - Jian Zhang
- Department for Vascular Surgery, First Hospital of China Medical University, Shenyang, China
| | - Xiaotong Song
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian, China
| | - Qingyang Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian, China
| | - Chen Chen
- School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | - Yanshuo Han
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian, China.
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Hou W, Hao Y, Yang W, Tian T, Fang P, Du Y, Gao L, Gao Y, Zhang Q. The Jieduan-Niwan (JDNW) Formula Ameliorates Hepatocyte Apoptosis: A Study of the Inhibition of E2F1-Mediated Apoptosis Signaling Pathways in Acute-on-Chronic Liver Failure (ACLF) Using Rats. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:3845-3862. [PMID: 34526765 PMCID: PMC8436178 DOI: 10.2147/dddt.s308713] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/04/2021] [Indexed: 12/29/2022]
Abstract
Background Acute-on-chronic liver failure (ACLF) is a severe, complicated human disease. E2F1-mediated apoptosis plays an important role in ACLF development. Jieduan-Niwan (JDNW) formula, a traditional Chinese medicine (TCM), has shown remarkable clinical efficacy in ACLF treatment. However, the hepatoprotective mechanisms of the formula are barely understood. Purpose This study aimed to investigate the mechanisms of JDNW formula in ACLF treatment by specifically regulating E2F1-mediated apoptotic signaling pathways in rats. Methods The JDNW components were determined by high-performance liquid chromatography (HPLC) analysis. The ACLF rat model was established using human serum albumin immune-induced liver cirrhosis, followed by D-galactosamine and lipopolysaccharide joint acute attacks. The ACLF rat was treated with JDNW formula. Prothrombin time activity was measured to investigate the coagulation function. Liver pathological injury was observed by hematoxylin-eosin (HE) and reticular fiber staining. The hepatocyte apoptosis index and apoptosis rate were determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and flow cytometry, respectively. Additionally, the expression of key genes and proteins that regulate E2F1-mediated apoptosis was analyzed by quantitative real-time PCR and Western blot. Results Seven major components of JDNW formula were detected. The formula ameliorated the coagulation function, decreased the hepatocyte apoptosis index and apoptosis rate, and alleviated liver pathological damage in ACLF rats. The down-regulation of the expression of genes and proteins from p53-dependent and non-p53-dependent apoptosis pathways and the up-regulation of the expression of genes from blocking anti-apoptotic signaling pathways indicated that JDNW formula inhibited excessive hepatocyte apoptosis in ACLF rats via E2F1-mediated apoptosis signaling pathways. Conclusion The findings indicate that JDNW formula protects livers of ACLF rats by inhibiting E2F1-mediated apoptotic signaling pathways, implying that these pathways might be a potential therapeutic target for ACLF treatment.
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Affiliation(s)
- Weixin Hou
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China.,Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Endocrinology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Yulin Hao
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Wenlong Yang
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Tian Tian
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Peng Fang
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Yuqiong Du
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Lianyin Gao
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Yanbin Gao
- Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Endocrinology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
| | - Qiuyun Zhang
- Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.,Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China
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p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies. Cancers (Basel) 2021; 13:cancers13122885. [PMID: 34207603 PMCID: PMC8227208 DOI: 10.3390/cancers13122885] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The p53 family of proteins comprises p53, p63, and p73, which share high structural and functional similarity. The two distinct promoters of each locus, the alternative splicing, and the alternative translation initiation sites enable the generation of numerous isoforms with different protein-interacting domains and distinct activities. The co-expressed p53/p73 isoforms have significant but distinct roles in carcinogenesis. Their activity is frequently impaired in human tumors including colorectal carcinoma due to dysregulated expression and a dominant-negative effect accomplished by some isoforms and p53 mutants. The interactions between isoforms are particularly important to understand the onset of tumor formation, progression, and therapeutic response. The understanding of the p53/p73 network can contribute to the development of new targeted therapies. Abstract The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each family member possesses two promoters and alternative translation initiation sites, and they undergo alternative splicing, generating multiple isoforms. The resulting isoforms have important roles in carcinogenesis, while their expression is dysregulated in several human tumors including colorectal carcinoma, which makes them potential targets in cancer treatment. Their activities arise, at least in part, from the ability to form tetramers that bind to specific DNA sequences and activate the transcription of target genes. In this review, we summarize the current understanding of the biological activities and regulation of the p53/p73 isoforms, highlighting their role in colorectal tumorigenesis. The analysis of the expression patterns of the p53/p73 isoforms in human cancers provides an important step in the improvement of cancer therapy. Furthermore, the interactions among the p53 family members which could modulate normal functions of the canonical p53 in tumor tissue are described. Lastly, we emphasize the importance of clinical studies to assess the significance of combining the deregulation of different members of the p53 family to define the outcome of the disease.
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31
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Zhou M, Xu Q, Huang D, Luo L. Regulation of gene transcription of B lymphoma Mo-MLV insertion region 1 homolog (Review). Biomed Rep 2021; 14:52. [PMID: 33884195 PMCID: PMC8056379 DOI: 10.3892/br.2021.1428] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 02/19/2021] [Indexed: 12/18/2022] Open
Abstract
B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is a core protein component of the polycomb repressive complex 1 that inhibits cell senescence and maintains the self-renewal ability of stem cells via downregulation of p16Ink4a and p19Arf expression. Bmi-1 serves an important role in hematopoietic stem cell maintenance and neurodevelopment during embryonic development, and it has been shown to enhance tumorigenesis by promoting cancer stem cell self-renewal and epithelial to mesenchymal transition. Emerging evidence suggests that Bmi-1 overexpression is closely related to the development and progression of various types of cancer, and that downregulation of Bmi-1 expression can inhibit the proliferation, invasion and metastasis of cancer cells. It is therefore important to elucidate the mechanisms underlying the regulation of Bmi-1 expression both under normal growth conditions and in malignant tissues. In the present review, the current body of knowledge pertaining to the transcriptional and post-transcriptional regulation of the BMI-1 gene is discussed, and the potential mechanisms by which Bmi-1 is dysregulated in various types of cancer are highlighted. Bmi-1 expression is primarily controlled via transcriptional regulation, and is regulated by the transcription https://www.ushuaia.pl/hyphen/?ln=en factors of the Myc family, including Myb, Twist1, SALL4 and E2F-1. Post-transcriptionally, regulation of Bmi-1 expression is inhibited by several microRNAs and certain small-molecule drugs. Thus, regulatory transcriptional factors are potential therapeutic targets to reduce Bmi-1 expression in cancer cells. Thus, the present review provides an up-to-date review on the regulation of BMI-1 gene expression at the transcriptional and post-transcriptional level.
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Affiliation(s)
- Meizhen Zhou
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qichao Xu
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Deqiang Huang
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Lingyu Luo
- Department of Gastroenterology, Research Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Ertosun MG, DİlmaÇ S, Hapİl FZ, TanriÖver G, KÖksoy S, ÖzeŞ ON. Regulation of E2F1 activity via PKA-mediated phosphorylations. ACTA ACUST UNITED AC 2020; 44:215-229. [PMID: 33110360 PMCID: PMC7585165 DOI: 10.3906/biy-2003-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 08/10/2020] [Indexed: 11/06/2022]
Abstract
E2F1 becomes activated during the G1 phase of the cell cycle, and posttranslational modifications modulate its activity. Activation of G-protein coupled receptors (GPCR) by many ligands induces the activation of adenylate cyclases and the production of cAMP, which activates the PKA enzyme. Activated PKA elicits its biological effect by phosphorylating the target proteins containing serine or threonine amino acids in the RxxS/T motif. Since PKA activation negatively regulates cell proliferation, we thought that activated PKA would negatively affect the activity of E2F1. In line with this, when we analyzed the amino acid sequence of E2F1, we found 3 hypothetical consensus PKA phosphorylation sites located at 127-130, 232-235, and 361-364 positions and RYET, RLLS, and RMGS sequences. After showing the binding and phosphorylation of E2F1 by PKA, we converted the codons of Threonine-130, Serine-235, and Serine-364 to Alanine and Glutamic acid codons on the eukaryotic E2F1 expression vector we had previously created. We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence.
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Affiliation(s)
- Mustafa Gökhan Ertosun
- Department of Plastic, Reconstructive, and Aesthetic Surgery, Faculty of Medicine, Akdeniz University, Antalya Turkey
| | - Sayra DİlmaÇ
- Department of Histology and Embriology, Faculty of Medicine, Akdeniz University, Antalya Turkey
| | - Fatma Zehra Hapİl
- Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya Turkey
| | - Gamze TanriÖver
- Department of Histology and Embriology, Faculty of Medicine, Akdeniz University, Antalya Turkey
| | - Sadi KÖksoy
- Department of Medical Microbiology, Faculty of Medicine, Akdeniz University, Antalya Turkey
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Saadat KA, Bozgeyik E, Arman K, Bozgeyik I, Ikeda MA. ARID3A-mediated modulation of TP73 and TP73-AS1 in osteosarcoma cells. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Skorobagatko DA, Mazilov AA, Strashnyuk VY. Endoreduplication in Drosophila melanogaster progeny after exposure to acute γ-irradiation. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2020; 59:211-220. [PMID: 31927628 DOI: 10.1007/s00411-019-00828-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 12/21/2019] [Indexed: 06/10/2023]
Abstract
The purpose of this investigation was to study the effect of acute γ-irradiation of parent adults on the endoreduplication of giant chromosomes in F1 generation of Drosophila melanogaster Meig. A wild-type Oregon-R strain was used as the material. Virgin females and males of Drosophila adults at the age of 3 days were irradiated with doses of 8, 16 and 25 Gy. Giant chromosomes were studied by cytomorphometry on squashed preparations of Drosophila salivary glands stained with acetoorsein. The preparations were obtained at late third instar larvae. The mean values of the polyteny degree of chromosomes (PDC) in males increased after 8 Gy by 10.6%, after 25 Gy by 7.4%, and did not change after the dose of 16 Gy. In females, the PDC did not differ from the control irrespective of the irradiation dose. An increase in endoreduplication was also evidenced by the accelerated development of offsprings of both sexes after irradiation of parents with 25 Gy, and in males also at a dose of 16 Gy. The statistical impact of power of radiation on polyteny was 26.8%, while the impact of sex was 4.9%. The impact of power of radiation on the developmental rate of offspring was 4.4% in males and 7.5% in females. The enhancement of endoreduplication is considered as a consequence of increasing selection pressure after irradiation. The possible involvement of epigenetic effects in the effect of ionizing radiation on endoreduplication is discussed.
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Affiliation(s)
- Daria A Skorobagatko
- Department of Genetics and Cytology, VN Karazin Kharkiv National University, Svobody sq., 4, Kharkiv, 61022, Ukraine
- Laboratory of Radiation Research and Environmental Protection, NSC 'Kharkiv Institute of Physics and Technology', Academicheskaya str., 1, Kharkiv, 61108, Ukraine
| | - Alexey A Mazilov
- Laboratory of Radiation Research and Environmental Protection, NSC 'Kharkiv Institute of Physics and Technology', Academicheskaya str., 1, Kharkiv, 61108, Ukraine
| | - Volodymyr Yu Strashnyuk
- Department of Genetics and Cytology, VN Karazin Kharkiv National University, Svobody sq., 4, Kharkiv, 61022, Ukraine.
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Hua B, Li Y, Yang X, Niu X, Zhao Y, Zhu X. MicroRNA-361-3p promotes human breast cancer cell viability by inhibiting the E2F1/P73 signalling pathway. Biomed Pharmacother 2020; 125:109994. [PMID: 32092817 DOI: 10.1016/j.biopha.2020.109994] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 01/20/2020] [Accepted: 02/03/2020] [Indexed: 01/26/2023] Open
Abstract
Analysis of the microRNA (miRNA) expression signature of breast cancer based on RNA sequencing demonstrated that miR-361-3p was significantly upregulated in breast cancer tissues. miR-361-3p is a novel miRNA, and its role in breast cancer is currently unclear. The aim of the present study was to investigate the functions of miR-361-3p in breast carcinoma. In this study, it was observed that the expression of miR-361-3p in cancer tissues was significantly higher compared with that in para-cancerous tissues and was correlated with advanced TNM stage, Ki-67 overexpression and shorter disease-free survival. Overexpression of miR-361-3p promoted proliferation and inhibited apoptosis of breast cancer cells. Through RNA sequencing, multi-library retrieval, luciferase reporter assays, quantitative polymerase chain reaction analysis, western blotting and other methods, it was verified that E2F1 was directly downregulated by miR-361-3p. The knockdown of E2F1 by siRNA promoted breast cancer cell proliferation and inhibited apoptosis, similar to miR-361-3p. In addition, miR-361-3p was able to decrease the expression of P73 by targeting E2F1, whereas overexpression of P73 reversed the effect of miR-361-3p on the viability of breast cancer cell lines. Thus, the present study demonstrated that miR-361-3p acts as an oncomiR in breast cancer to promote proliferation and inhibit apoptosis through inhibiting the P73 pathway by downregulating E2F1 expression, which may uncover valuable prognostic factors or treatment targets.
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Affiliation(s)
- Bin Hua
- Breast Center, Beijing Institute of Geriatrics National Health Commission, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China.
| | - Yao Li
- Breast Center, Beijing Institute of Geriatrics National Health Commission, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China.
| | - Xin Yang
- Breast Center, Beijing Institute of Geriatrics National Health Commission, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China.
| | - Xiaojuan Niu
- Breast Center, Beijing Institute of Geriatrics National Health Commission, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China.
| | - Yanyang Zhao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics National Health Commission, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China.
| | - Xiaoquan Zhu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics National Health Commission, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, PR China.
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Antitumor Potential of Marine and Freshwater Lectins. Mar Drugs 2019; 18:md18010011. [PMID: 31877692 PMCID: PMC7024344 DOI: 10.3390/md18010011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/18/2019] [Accepted: 12/18/2019] [Indexed: 12/12/2022] Open
Abstract
Often, even the most effective antineoplastic drugs currently used in clinic do not efficiently allow complete healing due to the related toxicity. The reason for the toxicity lies in the lack of selectivity for cancer cells of the vast majority of anticancer agents. Thus, the need for new potent anticancer compounds characterized by a better toxicological profile is compelling. Lectins belong to a particular class of non-immunogenic glycoproteins and have the characteristics to selectively bind specific sugar sequences on the surface of cells. This property is exploited to exclusively bind cancer cells and exert antitumor activity through the induction of different forms of regulated cell death and the inhibition of cancer cell proliferation. Thanks to the extraordinary biodiversity, marine environments represent a unique source of active natural compounds with anticancer potential. Several marine and freshwater organisms, ranging from the simplest alga to the most complex vertebrate, are amazingly enriched in these proteins. Remarkably, all studies gathered in this review show the impressive anticancer effect of each studied marine lectin combined with irrelevant toxicity in vitro and in vivo and pave the way to design clinical trials to assess the real antineoplastic potential of these promising proteins. It provides a concise and precise description of the experimental results, their interpretation as well as the experimental conclusions that can be drawn.
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Zhang YX, Pan WY, Chen J. p53 and its isoforms in DNA double-stranded break repair. J Zhejiang Univ Sci B 2019; 20:457-466. [PMID: 31090271 DOI: 10.1631/jzus.b1900167] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
DNA double-stranded break (DSB) is one of the most catastrophic damages of genotoxic insult. Inappropriate repair of DNA DSBs results in the loss of genetic information, mutation, and the generation of harmful genomic rearrangements, which predisposes an organism to immunodeficiency, neurological damage, and cancer. The tumor repressor p53 plays a key role in DNA damage response, and has been found to be mutated in 50% of human cancer. p53, p63, and p73 are three members of the p53 gene family. Recent discoveries have shown that human p53 gene encodes at least 12 isoforms. Different p53 members and isoforms play various roles in orchestrating DNA damage response to maintain genomic integrity. This review briefly explores the functions of p53 and its isoforms in DNA DSB repair.
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Affiliation(s)
- Yu-Xi Zhang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wen-Ya Pan
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jun Chen
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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Yang W, Hao Y, Hou W, Fang X, Fang P, Jiang T, Ma C, Zhang Q. Jieduan-Niwan Formula Reduces Liver Apoptosis in a Rat Model of Acute-on-Chronic Liver Failure by Regulating the E2F1-Mediated Intrinsic Apoptosis Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2019; 2019:8108503. [PMID: 31827563 PMCID: PMC6885299 DOI: 10.1155/2019/8108503] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/28/2019] [Accepted: 08/24/2019] [Indexed: 01/11/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a serious and complicated disease that threatens human health because its pathogenesis is unclear, and the outcome of the current therapies has been less than satisfactory. A national famous doctor of traditional Chinese medicine, Qian Ying, created the Jieduan-Niwan Formula (JDNW), based on his long-term clinical experience. However, despite the good clinical outcome, the biological mechanism by which it works is unknown. In the current study, we established an ACLF rat model by administering human serum albumin (HSA) combined with D-galactosamine (D-GalN) and lipopolysaccharide (LPS) to explore the potential mechanism of JDNW in treating ACLF. The rats were treated with JDNW by administration of the model substances and sacrificed after 4, 8, and 12 h. Then we divided the rats into normal group, model at 4 h, model at 8 h, model at 12 h, JDNW at 4 h, JDNW at 8 h, and JDNW at 12 h. Biochemical and histopathological examinations were performed to compare the rats in different groups. Compared with the ACLF model group, expression levels of alanine transaminase, aspartate aminotransferase, total bilirubin, and TNF-α and IL-6 proteins were reduced in the JDNW group at the corresponding time points, the survival rates of rats were increased, and the pathological condition of the liver was improved. In addition, JDNW treatment improved the ultrastructure of hepatocytes and mitochondria and decreased the hepatocyte apoptosis index. E2F1, P53, P73, Apaf-1, p14ARF, caspase-3, caspase-6, and caspase-7 levels in the JDNW group were distinctly lower than those in the untreated rats. Moreover, Bcl-2 and Mcl-1 levels increased. Thus, JDNW decreases ACLF-induced mortality in rats by modulating the E2F1-mediated intrinsic apoptotic pathway.
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Affiliation(s)
- Wenlong Yang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Yulin Hao
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Weixin Hou
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xian Fang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Peng Fang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Tianyuan Jiang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Chongyang Ma
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Qiuyun Zhang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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Naseer F, Saleem M. Epigenetic modification in the expression of p73 p73 - epigenetic target for anticancer therapy. Oncol Rev 2019; 13:421. [PMID: 31410249 PMCID: PMC6661529 DOI: 10.4081/oncol.2019.421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 06/10/2019] [Indexed: 11/22/2022] Open
Abstract
A p73 is a new member of p53 family of transcription factor, having two types. First is TAp73, transcriptionally active and expressed via upstream promoter as a tumor suppressor and vital apoptotic inductor, it also has a key role in cell cycle arrest/differentiation and Second is ΔNp73 that is transcriptionally inactive and expressed via downstream regulator as oncogenes. Both types are expressed in various isoforms, which originate from alternative splicing events at the C-terminus. Upon DNA damage, posttranslational modifications cause conformational changes in various amino acid residues via induction or inhibition of various proteins, which are present in the structural domains of p73. These modifications may cause up- or down-regulation of p73 expression levels, as well as alters the transcriptional activity and/or stability of the protein. In this review, we have made an effort to assemble all existing data regarding the role of p73, its modification and after effects in cancer.
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Affiliation(s)
- Faiza Naseer
- Shifa College of Pharmaceutical Sciences, Shifa Tameer e Millat University, Islamabad, Pakistan
| | - Mohammad Saleem
- Faculty of Pharmaceutical Sciences, Punjab University, Lahore, Pakistan
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Programmed expression of pro-apoptotic BMCC1 during apoptosis, triggered by DNA damage in neuroblastoma cells. BMC Cancer 2019; 19:542. [PMID: 31170959 PMCID: PMC6555734 DOI: 10.1186/s12885-019-5772-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/29/2019] [Indexed: 11/10/2022] Open
Abstract
Background The multi-functional BMCC1 (BCH motif-containing molecule at the carboxyl terminal region 1)/PRUNE2 plays a clear role in suppression of tumor activity. In the patients with neuroblastoma (NB), reduced expression of BMCC1 in primary tumor tissues was associated with poor prognosis. By contrast, enforced expression of BMCC1 as well as elevated expression of BMCC1 in response to DNA-damage promotes apoptosis by abrogating Akt-mediated survival pathways. Methods We addressed molecular mechanisms underlying changes in regulation of BMCC1 expression during the process of apoptosis, which was promoted by a DNA-damaging drug Cisplatin (CDDP), in NB-derived cells. Results Elevated expression of BMCC1 was identified as an early response to DNA damage, which is accompanied by phosphorylation of ataxia telangiectasia mutated kinase (ATM) and accumulation of E2F1. Indeed, inhibition of ATM using an ATM inhibitor resulted in a decrease in expression of BMCC1 at mRNA levels. In addition, an E2F-binding sight was required for activation of BMCC1 promoter in response to DNA damage. On the other hand, knockdown of E2F1 yielded abrogated induction of BMCC1 in the cells after treatment with CDDP, suggesting that BMCC1 accumulation was caused by ATM-E2F1-dependent transcription. Finally, we demonstrated that full-length BMCC1 was proteolytically cleaved by apoptosis-activated caspase-9 during advanced stages of apoptosis in SK-N-AS cells. Conclusions In this study, we demonstrated the programmed expression of full-length BMCC1 in human NB cells undergoing DNA damage-induced apoptosis. The elucidation of the molecular mechanisms controlling the regulation of BMCC1 during apoptosis initiated by DNA damage provides useful information for understanding drug resistance of tumor cells and spontaneous regression of NB. Electronic supplementary material The online version of this article (10.1186/s12885-019-5772-4) contains supplementary material, which is available to authorized users.
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Abstract
Differentiated neurons can undergo cell cycle re-entry during pathological conditions, but it remains largely accepted that M-phase is prohibited in these cells. Here we show that primary neurons at post-synaptogenesis stages of development can enter M-phase. We induced cell cycle re-entry by overexpressing a truncated Cyclin E isoform fused to Cdk2. Cyclin E/Cdk2 expression elicits canonical cell cycle checkpoints, which arrest cell cycle progression and trigger apoptosis. As in mitotic cells, checkpoint abrogation enables cell cycle progression through S and G2-phases into M-phase. Although most neurons enter M-phase, only a small subset undergo cell division. Alternatively, neurons can exit M-phase without cell division and recover the axon initial segment, a structural determinant of neuronal viability. We conclude that neurons and mitotic cells share S, G2 and M-phase regulation.
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Gu Y, Wang X, Liu H, Li G, Yu W, Ma Q. SET7/9 promotes hepatocellular carcinoma progression through regulation of E2F1. Oncol Rep 2018; 40:1863-1874. [PMID: 30106440 PMCID: PMC6111541 DOI: 10.3892/or.2018.6621] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 07/06/2018] [Indexed: 01/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Histone‑lysine N‑methyltransferase SET7/9 is a protein lysine monomethylase that methylates histone H3K4 as well as various non‑histone proteins. Deregulation of SET7/9 is frequently detected in human cancers. However, the role of SET7/9 in HCC development remains unclear. In the present study, upregulation of SET7/9 and E2F transcription factor 1 (E2F1) expression was detected in 68 samples of HCC tissues compared with these levels noted in the paired healthy liver samples. The expression levels of SET7/9 and E2F1 were significantly correlated with pathological stage and tumor size. Subcellular fractionation and co‑immunoprecipitation analyses revealed protein‑protein interaction between SET7/9 and E2F1 in the cytoplasm of HCC cells. Silencing of SET7/9, as well as treatment with 5'‑deoxy‑5'‑methylthioadenosine (MTA), a protein methylation inhibitor, led to reduced E2F1 protein abundance in HCC cells. Using Cell Counting Kit‑8 (CCK‑8) assay, Transwell migration assay and wound healing assay, significantly decreased cell proliferation, migration and invasion were observed in cells exhibiting downregulation of SET7/9 and E2F1 expression, as well as in wild‑type HCC cells treated with MTA. Furthermore, SET7/9 downregulation and MTA treatment resulted in reduced expression of downstream targets of E2F1, including cyclin A2, cyclin E1 and CDK2. In conclusion, the present study revealed an oncogenic function of SET7/9 in HCC and demonstrated that SET7/9 may be responsible for alterations in the proliferative ability, aggressiveness and invasive/metastatic potential of HCC cells through post‑translational regulation of E2F1.
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Affiliation(s)
- Ye Gu
- Department of Pathophysiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, P.R. China
| | - Xinling Wang
- Department of Pathology, No. 81 Hospital of PLA, Nanjing, Jiangsu 210002, P.R. China
| | - Hong Liu
- Department of Pathophysiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, P.R. China
| | - Guimei Li
- Department of Pathology, No. 81 Hospital of PLA, Nanjing, Jiangsu 210002, P.R. China
| | - Weiping Yu
- Department of Pathophysiology, Medical School of Southeast University, Nanjing, Jiangsu, 210009, P.R. China
| | - Qing Ma
- College of Biological and Environmental Engineering, Zhejiang Shuren University, Hangzhou, Zhejiang 310015, P.R. China
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Ozaki T, Yu M, Yin D, Sun D, Zhu Y, Bu Y, Sang M. Impact of RUNX2 on drug-resistant human pancreatic cancer cells with p53 mutations. BMC Cancer 2018; 18:309. [PMID: 29558908 PMCID: PMC5861661 DOI: 10.1186/s12885-018-4217-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 03/12/2018] [Indexed: 12/20/2022] Open
Abstract
Background Despite the remarkable advances in the early diagnosis and treatment, overall 5-year survival rate of patients with pancreatic cancer is less than 10%. Gemcitabine (GEM), a cytidine nucleoside analogue and ribonucleotide reductase inhibitor, is a primary option for patients with advanced pancreatic cancer; however, its clinical efficacy is extremely limited. This unfavorable clinical outcome of pancreatic cancer patients is at least in part attributable to their poor response to anti-cancer drugs such as GEM. Thus, it is urgent to understand the precise molecular basis behind the drug-resistant property of pancreatic cancer and also to develop a novel strategy to overcome this deadly disease. Review Accumulating evidence strongly suggests that p53 mutations contribute to the acquisition and/or maintenance of drug-resistant property of pancreatic cancer. Indeed, certain p53 mutants render pancreatic cancer cells much more resistant to GEM, implying that p53 mutation is one of the critical determinants of GEM sensitivity. Intriguingly, runt-related transcription factor 2 (RUNX2) is expressed at higher level in numerous human cancers such as pancreatic cancer and osteosarcoma, indicating that, in addition to its pro-osteogenic role, RUNX2 has a pro-oncogenic potential. Moreover, a growing body of evidence implies that a variety of miRNAs suppress malignant phenotypes of pancreatic cancer cells including drug resistance through the down-regulation of RUNX2. Recently, we have found for the first time that forced depletion of RUNX2 significantly increases GEM sensitivity of p53-null as well as p53-mutated pancreatic cancer cells through the stimulation of p53 family TAp63/TAp73-dependent cell death pathway. Conclusions Together, it is likely that RUNX2 is one of the promising molecular targets for the treatment of the patients with pancreatic cancer regardless of their p53 status. In this review article, we will discuss how to overcome the serious drug-resistant phenotype of pancreatic cancer.
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Affiliation(s)
- Toshinori Ozaki
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan.
| | - Meng Yu
- Department of Laboratory Animal of China Medical University, Shenyang, 110001, People's Republic of China
| | - Danjing Yin
- Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, People's Republic of China
| | - Dan Sun
- Department of Urology, First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Yuyan Zhu
- Department of Urology, First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Youquan Bu
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Meixiang Sang
- Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, People's Republic of China
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p73 coordinates with Δ133p53 to promote DNA double-strand break repair. Cell Death Differ 2018; 25:1063-1079. [PMID: 29511339 PMCID: PMC5988805 DOI: 10.1038/s41418-018-0085-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 01/18/2018] [Accepted: 02/07/2018] [Indexed: 12/16/2022] Open
Abstract
Tumour repressor p53 isoform Δ133p53 is a target gene of p53 and an antagonist of p53-mediated apoptotic activity. We recently demonstrated that Δ133p53 promotes DNA double-strand break (DSB) repair by upregulating transcription of the repair genes RAD51, LIG4 and RAD52 in a p53-independent manner. However, Δ133p53 lacks the transactivation domain of full-length p53, and the mechanism by which it exerts transcriptional activity independently of full-length p53 remains unclear. In this report, we describe the accumulation of high levels of both Δ133p53 and p73 (a p53 family member) at 24 h post γ-irradiation (hpi). Δ133p53 can form a complex with p73 upon γ-irradiation. The co-expression of Δ133p53 and p73, but not either protein alone, can significantly promote DNA DSB repair mechanisms, including homologous recombination (HR), non-homologous end joining (NHEJ) and single-strand annealing (SSA). p73 and Δ133p53 act synergistically to promote the expression of RAD51, LIG4 and RAD52 by joining together to bind to region containing a Δ133p53-responsive element (RE) and a p73-RE in the promoters of all three repair genes. In addition to its accumulation at 24 hpi, p73 protein expression also peaks at 4 hpi. The depletion of p73 not only reduces early-stage apoptotic frequency (4–6 hpi), but also significantly increases later-stage DNA DSB accumulation (48 hpi), leading to cell cycle arrest in the G2 phase and, ultimately, cell senescence. In summary, the apoptotic regulator p73 also coordinates with Δ133p53 to promote DNA DSB repair, and the loss of function of p73 in DNA DSB repair may underlie spontaneous and carcinogen-induced tumorigenesis in p73 knockout mice.
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Ozaki T, Nakamura M, Ogata T, Sang M, Yoda H, Hiraoka K, Sang M, Shimozato O. Depletion of pro-oncogenic RUNX2 enhances gemcitabine (GEM) sensitivity of p53-mutated pancreatic cancer Panc-1 cells through the induction of pro-apoptotic TAp63. Oncotarget 2018; 7:71937-71950. [PMID: 27713122 PMCID: PMC5342134 DOI: 10.18632/oncotarget.12433] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 09/25/2016] [Indexed: 12/13/2022] Open
Abstract
Recently, we have described that siRNA-mediated silencing of runt-related transcription factor 2 (RUNX2) improves anti-cancer drug gemcitabine (GEM) sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells through the augmentation of p53 family TAp63-dependent cell death pathway. In this manuscript, we have extended our study to p53-mutated human pancreatic cancer Panc-1 cells. According to our present results, knockdown of mutant p53 alone had a marginal effect on GEM-mediated cell death of Panc-1 cells. We then sought to deplete RUNX2 using siRNA in Panc-1 cells and examined its effect on GEM sensitivity. Under our experimental conditions, RUNX2 knockdown caused a significant enhancement of GEM sensitivity of Panc-1 cells. Notably, GEM-mediated induction of TAp63 but not of TAp73 was further stimulated in RUNX2-depleted Panc-1 cells, indicating that, like AsPC-1 cells, TAp63 might play a pivotal role in the regulation of GEM sensitivity of Panc-1 cells. Consistent with this notion, forced expression of TAp63α in Panc-1 cells promoted cell cycle arrest and/or cell death, and massively increased luciferase activities driven by TAp63-target gene promoters such as p21WAF1 and NOXA. In addition, immunoprecipitation experiments indicated that RUNX2 forms a complex with TAp63 in Panc-1 cells. Taken together, our current observations strongly suggest that depletion of RUNX2 enhances the cytotoxic effect of GEM on p53-mutated Panc-1 cells through the stimulation of TAp63-dependent cell death pathway even in the presence of a large amount of pro-oncogenic mutant p53, and might provide an attractive strategy to treat pancreatic cancer patients with p53 mutations.
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Affiliation(s)
- Toshinori Ozaki
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Mizuyo Nakamura
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Takehiro Ogata
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Meijie Sang
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan.,Department of Regenerative Medicine, Graduate School of Medicine and Pharmatheutical Science, University of Toyama, Toyama, Japan
| | - Hiroyuki Yoda
- Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Kiriko Hiraoka
- Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Meixiang Sang
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan.,Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Osamu Shimozato
- Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan
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Marine Lectins DlFBL and HddSBL Fused with Soluble Coxsackie-Adenovirus Receptor Facilitate Adenovirus Infection in Cancer Cells BUT Have Different Effects on Cell Survival. Mar Drugs 2017; 15:md15030073. [PMID: 28335432 PMCID: PMC5367030 DOI: 10.3390/md15030073] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/26/2017] [Accepted: 03/10/2017] [Indexed: 01/24/2023] Open
Abstract
Cancer development and progression are usually associated with glycosylation change, providing prognostic and diagnostic biomarkers, as well as therapeutic targets, for various cancers. In this work, Dicentrarchus labrax fucose binding lectin (DlFBL) and Haliotis discus discus sialic acid binding lectin (HddSBL) were genetically fused with soluble coxsackie-adenovirus receptor (sCAR), and produced through a bacterial expression system. Results showed that recombinant sCAR-DlFBL not only facilitated adenovirus Ad-EGFP infection in K562/ADR and U87MG cells, but also enhanced the cytotoxicity of adenovirus harboring gene encoding Pinellia pedatisecta agglutinin (PPA) or DlFBL (Ad-PPA or Ad-DlFBL) on U87MG cells through inducing apoptosis. Recombinant sCAR-HddSBL facilitated Ad-EGFP infection, but dramatically counteracted the cytotoxicity of both Ad-PPA and Ad-DlFBL in U87MG cells. Further analysis revealed that sCAR-HddSBL, but not sCAR-DlFBL, significantly upregulated transcription factor E2F1 levels in U87MG cells, which might be responsible for the adverse effect of sCAR-HddSBL on Ad-PPA and Ad-DlFBL. Taken together, our data suggested that sCAR-DlFBL could be further developed to redirect therapeutic adenoviruses to infect cancer cells such as U87MG, and the sCAR-lectin fusion proteins for adenoviral retargeting should be carefully examined for possible survival signaling induced by lectins, such as HddSBL.
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Hassan HM, Varney ML, Chaturvedi NK, Joshi SS, Weisenburger DD, Singh RK, Dave BJ. Modulation of p73 isoforms expression induces anti-proliferative and pro-apoptotic activity in mantle cell lymphoma independent of p53 status. Leuk Lymphoma 2016; 57:2874-2889. [PMID: 27074052 PMCID: PMC5967247 DOI: 10.3109/10428194.2016.1165814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapse and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome. In this report, we investigated whether modulation of p73 isoforms by diclofenac inhibits cell growth, induces apoptosis and/or cell cycle arrest in MCL relative to p53 status. Wild-type p53 [Granta-519 and JVM-2], mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines, and primary human cells isolated from MCL patients were used. Overexpression of pro-apoptotic TAp73 enhanced MCL cell apoptosis. Diclofenac induced a concentration- and duration-dependent increase in TAp73, cell cycle arrest, cell death, and inhibited MCL cell growth independent of p53 status. Diclofenac treatment was associated with increased activity of caspases 3, 7, and 8 and induction of p53 transcriptional target genes. These studies demonstrate the potential for diclofenac as novel therapeutic agent in MCL independent of p53 status.
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Affiliation(s)
- Hesham M. Hassan
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michelle L. Varney
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Nagendra K. Chaturvedi
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shantaram S. Joshi
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Rakesh K. Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bhavana J. Dave
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
- Human Genetics Laboratories, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA
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He H, Wang C, Dai Q, Li F, Bergholz J, Li Z, Li Q, Xiao ZX. p53 and p73 Regulate Apoptosis but Not Cell-Cycle Progression in Mouse Embryonic Stem Cells upon DNA Damage and Differentiation. Stem Cell Reports 2016; 7:1087-1098. [PMID: 27866875 PMCID: PMC5161534 DOI: 10.1016/j.stemcr.2016.10.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 10/21/2016] [Accepted: 10/24/2016] [Indexed: 01/23/2023] Open
Abstract
Embryonic stem cells (ESCs) are fast proliferating cells capable of differentiating into all somatic cell types. In somatic cells, it is well documented that p53 is rapidly activated upon DNA damage to arrest the cell cycle and induce apoptosis. In mouse ESCs, p53 can also be functionally activated, but the precise biological consequences are not well characterized. Here, we demonstrated that doxorubicin treatment initially led to cell-cycle arrest at G2/M in ESCs, followed by the occurrence of massive apoptosis. Neither p53 nor its target gene p73 was required for G2/M arrest. Instead, p53 and p73 were fully responsible for apoptosis. p53 and p73 were also required for differentiation-induced apoptosis in mouse ESCs. In addition, doxorubicin treatment induced the expression of retinoblastoma protein in a p53-dependent manner. Therefore, both p53 and p73 are critical in apoptosis induced by DNA damage and differentiation.
p53/p73 are key for DNA damage-induced apoptosis but not G2/M arrest in mESCs Both p53 and p73 are required for differentiation-induced apoptosis in mESCs Doxorubicin induces RB via p53-mediated suppression of miR-17-92 and miR-106a-363 p73 expression is induced upon differentiation in mESCs
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Affiliation(s)
- Hanbing He
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, 19 Wang Jang Road, Chengdu 610064, China
| | - Cheng Wang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, 19 Wang Jang Road, Chengdu 610064, China
| | - Qian Dai
- Department of Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu 610041, China
| | - Fengtian Li
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, 19 Wang Jang Road, Chengdu 610064, China
| | - Johann Bergholz
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, 19 Wang Jang Road, Chengdu 610064, China
| | - Zhonghan Li
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, 19 Wang Jang Road, Chengdu 610064, China
| | - Qintong Li
- Department of Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu 610041, China.
| | - Zhi-Xiong Xiao
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, 19 Wang Jang Road, Chengdu 610064, China.
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Transcriptional regulation of BMCC1 mediated by E2F1 in neuroblastoma cells. Biochem Biophys Res Commun 2016; 478:81-86. [DOI: 10.1016/j.bbrc.2016.07.089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 07/20/2016] [Indexed: 01/15/2023]
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50
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Lo PK, Lee JS, Liang X, Sukumar S. The dual role of FOXF2 in regulation of DNA replication and the epithelial-mesenchymal transition in breast cancer progression. Cell Signal 2016; 28:1502-19. [PMID: 27377963 DOI: 10.1016/j.cellsig.2016.06.021] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 06/13/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023]
Abstract
Dysregulation of Forkhead-box (FOX) transcription factors is linked to cancers of numerous tissue types. Here, we report that FOXF2 is frequently silenced in luminal-type and HER2-positive breast cancers, but is overexpressed in basal-like breast cancers; thus, FOXF2 appears to play distinct roles in different breast cancer subtypes. Inactivation of FOXF2 in luminal-type and HER2-positive breast cancers is attributable to epigenetic silencing. Silencing of FOXF2 is associated with poor prognosis in luminal-type breast cancer. Ectopic expression of FOXF2 in luminal and HER2-positive breast cancer cells suppresses their tumorigenic properties in vitro and in vivo via inhibition of the CDK2-RB-E2F cascade. The in vivo function of FOXF2 is to maintain the stringency of DNA replication, and its loss triggers dysregulation of DNA replication, which in turn activates the p53 checkpoint pathway. Besides its role in cell cycle regulation, FOXF2 is functionally required for mobility and epithelial-to-mesenchymal transition (EMT) of normal breast epithelial cells. In basal-like breast cancer cells, the cell-cycle function of FOXF2 is impaired. However, the EMT function of FOXF2 is still required for mobility, invasiveness and anchorage-independent growth of basal-like breast cancer cells. Our gene expression profiling studies demonstrate that FOXF2 regulates the expression of genes implicated in cell cycle and EMT regulation. Moreover, FOXF2 is highly co-expressed with basal- and metastasis-related genes in breast cancer. These findings suggest that FOXF2 has a dual role in breast tumorigenesis and functions as either a tumor suppressor or an oncogene depending on the breast tumor subtype.
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Affiliation(s)
- Pang-Kuo Lo
- Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Ji Shin Lee
- Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xiaohui Liang
- Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Saraswati Sukumar
- Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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