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Mani R, Benrashid S, Templeton MD, Druhan LJ, Seegers SL, Chakraborty S, Teague SE, Jaros SC, Yang HT, Foureau DM, Steuerwald NM, Pal D, Ghosh N, Copelan EA, Durden DL, Avalos BR, Park SI. TP53 upregulation via aurora kinase inhibition overcomes primary failure to venetoclax in BCL2-rearranged lymphomas. iScience 2025; 28:112584. [PMID: 40491476 PMCID: PMC12146551 DOI: 10.1016/j.isci.2025.112584] [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: 01/31/2024] [Revised: 12/04/2024] [Accepted: 03/29/2025] [Indexed: 06/11/2025] Open
Abstract
Bcl2 inhibition has excellent antitumor activity against hematologic malignancies. However, the clinical results in lymphomas harboring BCL2 gene rearrangements have been disappointing, and the mechanism of this intrinsic resistance remains unknown. Herein, we report that Bcl2 inhibition rapidly repressed p53 with poor response in BCL2-rearranged lymphoma cells. However, concurrent inhibition of aurora kinase (Aurk) overcame this primary resistance to Bcl2 inhibition by restoring the p53/p21 proapoptotic axis via a post-transcriptional increase in p53. Two independent BCL2-rearranged lymphoma murine models showed complete tumor regression in all animals treated with combined Bcl2/Aurk inhibition, whereas mice treated with single-agents demonstrated rapid progression. Transcriptome analysis confirmed that BCL2-rearranged lymphomas rapidly downregulated the p53 target CDKN1A (p21) in response to Bcl2 inhibition in vivo. However, concurrent inhibition of Aurk restored the TP53/CDKN1A pathway, sensitizing the tumors to Bcl2 inhibitor-mediated apoptosis. These data lay the groundwork for evaluation of this combination in the clinical setting.
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Affiliation(s)
- Rajeswaran Mani
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Samon Benrashid
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Margaret D. Templeton
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Lawrence J. Druhan
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Sara L. Seegers
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Supriya Chakraborty
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Sarah E. Teague
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Scott C. Jaros
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Hsih-Te Yang
- Center for Cancer Biostatistics, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - David M. Foureau
- Immune Monitoring Laboratory, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Nury M. Steuerwald
- Molecular Biology and Genomics Laboratory, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Dhananjaya Pal
- Molecular Targeted Therapeutics, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
| | - Nilanjan Ghosh
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Edward A. Copelan
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Donald L. Durden
- Molecular Targeted Therapeutics, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Belinda R. Avalos
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Steven I. Park
- Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC 28204, USA
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
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Baba Y, Sakai H, Maeda N, Abe M, Kabasawa N, Fukuda T. Acute Myeloid Leukemia with MYC Amplification on a Ring Chromosome 8. Intern Med 2025:5171-24. [PMID: 40254434 DOI: 10.2169/internalmedicine.5171-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/22/2025] Open
Abstract
MYC amplification and overexpression are uncommon in acute myeloid leukemia (AML). An 82-year-old man developed leukocytosis during monoclonal gammopathy of renal significance. A chromosomal analysis revealed 46,XY,+r(8)[20]. Amplified MYC signals were detected on chromosome 8. The patient was diagnosed with AML and administered venetoclax and azacitidine. After the third course, clones with ring chromosome 8 had decreased in number, but clones unrelated to t(8;21)(q22;q22) had subsequently emerged. After the sixth course, the white blood cell count had markedly increased, and a chromosome analysis showed replacement of ring chromosome 8 with 46,XY,t(8;21)[20]. This case highlights the role of MYC amplification and overexpression in AML and suggests that BCL2 inhibition is a potential treatment.
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Affiliation(s)
- Yuta Baba
- Division of Hematology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Hirotaka Sakai
- Division of Hematology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Nodoka Maeda
- Division of Hematology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Maasa Abe
- Division of Hematology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Nobuyuki Kabasawa
- Division of Hematology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Tetsuya Fukuda
- Division of Hematology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
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Croce CM, Vaux D, Strasser A, Opferman JT, Czabotar PE, Fesik SW. The BCL-2 protein family: from discovery to drug development. Cell Death Differ 2025:10.1038/s41418-025-01481-z. [PMID: 40204952 DOI: 10.1038/s41418-025-01481-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/24/2025] [Accepted: 03/14/2025] [Indexed: 04/11/2025] Open
Abstract
The landmark discovery of the BCL-2 gene and then its function marked the identification of inhibition of apoptotic cell death as a crucial novel mechanism driving cancer development and launched the quest to discover the molecular control of apoptosis. This work culminated in the generation of specific inhibitors that are now in clinical use, saving and improving tens of thousands of lives annually. Here, some of the original players of this story, describe the sequence of critical discoveries. The t(14;18) chromosomal translocation, frequently observed in follicular lymphoma, allowed the identification and the cloning of a novel oncogene (BCL-2) juxtaposed to the immunoglobulin heavy chain gene locus (IgH). Of note, BCL-2 acted in a distinct manner as compared to then already known oncogenic proteins like ABL and c-MYC. BCL-2 did not promote cell proliferation but inhibited cell death, as originally shown in growth factor dependent haematopoietic progenitor cell lines (e.g., FDC-P1) and in Eμ-Myc/Eμ-Bcl-2 double transgenic mice. Following a rapid expansion of the BCL-2 protein family, the Abbott Laboratories solved the first structure of BCL-XL and subsequently the BCL-XL/BAK peptide complex, opening the way to understanding the structures of other BCL-2 family members and, finally, to the generation of inhibitors of the different pro-survival BCL-2 proteins, thanks to the efforts of Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude and Gilead. Although the BCL-2 inhibitor Venetoclax is in clinical use and inhibitors of BCL-XL and MCL-1 are undergoing clinical trials, several questions remain on whether therapeutic windows can be achieved and what other agents should be used in combination with BH3 mimetics to achieve optimal therapeutic impact for cancer therapy. Finally, the control of the expression of BH3-only proteins and pro-survival BCL-2 family members needs to be better understood as this may identify novel targets for cancer therapy. This story is still not concluded!
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Affiliation(s)
- Carlo M Croce
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
| | - David Vaux
- The Walter and Eliza Hall Institute, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
| | - Andreas Strasser
- The Walter and Eliza Hall Institute, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
| | - Stephen W Fesik
- Department of Biochemistry, Pharmacology and Chemistry, Vanderbilt University, Nashville, TN, USA.
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Guiyedi K, Parquet M, Aoufouchi S, Chauzeix J, Rizzo D, Al Jamal I, Feuillard J, Gachard N, Peron S. Increased c-MYC Expression Associated with Active IGH Locus Rearrangement: An Emerging Role for c-MYC in Chronic Lymphocytic Leukemia. Cancers (Basel) 2024; 16:3749. [PMID: 39594704 PMCID: PMC11592262 DOI: 10.3390/cancers16223749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 10/25/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
This review examines the pivotal role of c-MYC in Chronic Lymphocytic Leukemia (CLL), focusing on how its overexpression leads to increased genetic instability, thereby accelerating disease progression. MYC, a major oncogene, encodes a transcription factor that regulates essential cellular processes, including cell cycle control, proliferation, and apoptosis. In CLL cases enriched with unmutated immunoglobulin heavy chain variable (IGHV) genes, MYC is significantly overexpressed and associated with active rearrangements in the IGH immunoglobulin heavy chain locus. This overexpression results in substantial DNA damage, including double-strand breaks, chromosomal translocations, and an increase in abnormal repair events. Consequently, c-MYC plays a dual role in CLL: it promotes aggressive cell proliferation while concurrently driving genomic instability through its involvement in genetic recombination. This dynamic contributes not only to CLL progression but also to the overall aggressiveness of the disease. Additionally, the review suggests that c-MYC's influence on genetic rearrangements makes it an attractive target for therapeutic strategies aimed at mitigating CLL malignancy. These findings underscore c-MYC's critical importance in advancing CLL progression, highlighting the need for further research to explore its potential as a target in future treatment approaches.
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Affiliation(s)
- Kenza Guiyedi
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
| | - Milène Parquet
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
| | - Said Aoufouchi
- Gustave Roussy, B-Cell and Genome Plasticity Team, CNRS UMR9019, Villejuif, France and Université Paris-Saclay, 91400 Orsay, France
| | - Jasmine Chauzeix
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
- Laboratoire d’Hématologie Biologique, Centre Hospitalier Universitaire de Limoges, 87000 Limoges, France
| | - David Rizzo
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
- Laboratoire d’Hématologie Biologique, Centre Hospitalier Universitaire de Limoges, 87000 Limoges, France
| | - Israa Al Jamal
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
- Faculty of Sciences, GSBT Genomic Surveillance and Biotherapy Team, Mont Michel Campus, Lebanese University, Tripoli 1300, Lebanon
| | - Jean Feuillard
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
- Laboratoire d’Hématologie Biologique, Centre Hospitalier Universitaire de Limoges, 87000 Limoges, France
| | - Nathalie Gachard
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
- Laboratoire d’Hématologie Biologique, Centre Hospitalier Universitaire de Limoges, 87000 Limoges, France
| | - Sophie Peron
- Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276/INSERM U1262, Université de Limoges, 87000 Limoges, France
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Chia JE, Rousseau RP, Ozturk M, Poswayo SKL, Lucas R, Brombacher F, Parihar SP. The divergent outcome of IL-4Rα signalling on Foxp3 T regulatory cells in listeriosis and tuberculosis. Front Immunol 2024; 15:1427055. [PMID: 39483462 PMCID: PMC11524857 DOI: 10.3389/fimmu.2024.1427055] [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: 05/02/2024] [Accepted: 09/18/2024] [Indexed: 11/03/2024] Open
Abstract
Introduction Forkhead box P3 (Foxp3) T regulatory cells are critical for maintaining self-tolerance, immune homeostasis, and regulating the immune system. Methods We investigated interleukin-4 receptor alpha (IL-4Rα) signalling on T regulatory cells (Tregs) during Listeria monocytogenes (L. monocytogenes) infection using a mouse model on a BALB/c background, specifically with IL-4Rα knockdown in Tregs (Foxp3creIL-4Rα-/lox). Results We showed an impairment of Treg responses, along with a decreased bacterial burden and diminished tissue pathology in the liver and spleen, which translated into better survival. Mechanistically, we observed an enhancement of the Th1 signature, characterised by increased expression of the T-bet transcription factor and a greater number of effector T cells producing IFN-γ, IL-2 following ex-vivo stimulation with heat-killed L. monocytogenes in Foxp3creIL-4Rα-/lox mice. Furthermore, CD8 T cells from Foxp3creIL-4Rα-/lox mice displayed increased cytotoxicity (Granzyme-B) with higher proliferation capacity (Ki-67), better survival (Bcl-2) with concomitant reduced apoptosis (activated caspase 3). In contrast to L. monocytogenes, Foxp3creIL-4Rα-/lox mice displayed similar bacterial burdens, lung pathology and survival during Mycobacterium tuberculosis (M. tuberculosis) infection, despite increased T cell numbers and IFN-γ, TNF and IL-17 production. Conclusion Our results demonstrated that the diminished IL-4Rα signalling on Foxp3+ T regulatory cells resulted in a loss of their functionality, leading to survival benefits in listeriosis but not in tuberculosis.
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Affiliation(s)
- Julius E. Chia
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Robert P. Rousseau
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Mumin Ozturk
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Sibongiseni K. L. Poswayo
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Rodney Lucas
- Research Animal Facility (RAF), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Suraj P. Parihar
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Division of Medical Microbiology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Division of Human Metabolomics, North-West University, Potchefstroom, South Africa
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Dehghani Z, Ranjbar S, Shahabinezhad F, Sabouri P, Mohammadi Bardbori A. A toxicogenomics-based identification of potential mechanisms and signaling pathways involved in PFCs-induced cancer in human. Toxicol Res (Camb) 2024; 13:tfae151. [PMID: 39323479 PMCID: PMC11420517 DOI: 10.1093/toxres/tfae151] [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: 12/18/2023] [Revised: 08/14/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024] Open
Abstract
Introduction The number of new diagnosed cancer cases and cancer deaths are increasing worldwide. Perfluorinated compounds (PFCs) are synthetic chemicals, which are possible inducers of cancer in human and laboratory animals. Studies showed that PFCs induce breast, prostate, kidney, liver and pancreas cancer by inducing genes being involved in carcinogenic pathways. Methodology This study reviews the association between PFCs induced up-regulation/down-regulation of genes and signaling pathways that are important in promoting different types of cancer. To obtain chemical-gene interactions, an advanced search was performed in the Comparative Toxicogenomics Database platform. Results Five most prevalent cancers were studied and the maps of their signaling pathways were drawn, and colored borders indicate significantly differentially expressed genes if there had been reports of alterations in expression in the presence of PFCs. Conclusion In general, PFCs are capable of inducing cancer in human via altering PPARα and PI3K pathways, evading apoptosis, inducing sustained angiogenesis, alterations in proliferation and blocking differentiation. However, more epidemiological data and mechanistic studies are needed to better understand the carcinogenic effects of PFCs in human.
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Affiliation(s)
- Zahra Dehghani
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz
University of Medical Sciences, Rokn Abad, Karafarin St., 7146864685,
Shiraz, Iran
| | - Sara Ranjbar
- Pharmaceutical Sciences Research Center, Shiraz University of Medical
Sciences, Rokn Abad, Karafarin St., 7146864685, Shiraz, Iran
| | - Farbod Shahabinezhad
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz
University of Medical Sciences, Rokn Abad, Karafarin St., 7146864685,
Shiraz, Iran
| | - Pooria Sabouri
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz
University of Medical Sciences, Rokn Abad, Karafarin St., 7146864685,
Shiraz, Iran
| | - Afshin Mohammadi Bardbori
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz
University of Medical Sciences, Rokn Abad, Karafarin St., 7146864685,
Shiraz, Iran
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Meena JK, Wang JH, Neill NJ, Keough D, Putluri N, Katsonis P, Koire AM, Lee H, Bowling EA, Tyagi S, Orellana M, Dominguez-Vidaña R, Li H, Eagle K, Danan C, Chung HC, Yang AD, Wu W, Kurley SJ, Ho BM, Zoeller JR, Olson CM, Meerbrey KL, Lichtarge O, Sreekumar A, Dacso CC, Guddat LW, Rejman D, Hocková D, Janeba Z, Simon LM, Lin CY, Pillon MC, Westbrook TF. MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer. Cancer Discov 2024; 14:1699-1716. [PMID: 39193992 PMCID: PMC11372365 DOI: 10.1158/2159-8290.cd-22-0649] [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: 07/21/2022] [Revised: 09/12/2023] [Accepted: 05/06/2024] [Indexed: 08/29/2024]
Abstract
Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers.
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Affiliation(s)
- Jitendra K. Meena
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Jarey H. Wang
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas.
| | - Nicholas J. Neill
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
| | - Dianne Keough
- The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
| | - Panagiotis Katsonis
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
| | - Amanda M. Koire
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
| | - Hyemin Lee
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Elizabeth A. Bowling
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Siddhartha Tyagi
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Mayra Orellana
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Rocio Dominguez-Vidaña
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Heyuan Li
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Kenneth Eagle
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
| | - Charles Danan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
| | - Hsiang-Ching Chung
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Andrew D. Yang
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas.
| | - William Wu
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas.
| | - Sarah J. Kurley
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Brian M. Ho
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas.
| | - Joseph R. Zoeller
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas.
| | - Calla M. Olson
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Kristen L. Meerbrey
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Olivier Lichtarge
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
| | - Arun Sreekumar
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
| | - Clifford C. Dacso
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
| | - Luke W. Guddat
- The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
| | - Dominik Rejman
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
| | - Dana Hocková
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
| | - Zlatko Janeba
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
| | - Lukas M. Simon
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
| | - Charles Y. Lin
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
| | - Monica C. Pillon
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
| | - Thomas F. Westbrook
- Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas.
- Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
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8
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Zhang W, Tao N, Bai L. Polysaccharides from Lentinus edodes prevent acquired drug resistance to docetaxel in prostate cancer cells by decreasing the TGF-β1 secretion of cancer-associated fibroblasts. J Nat Med 2023; 77:817-828. [PMID: 37354258 DOI: 10.1007/s11418-023-01722-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/11/2023] [Indexed: 06/26/2023]
Abstract
Prostate cancer is one of the most prevalent lethal diseases among men globally. In the treatment of prostate cancer, the limited therapeutic efficacy of the standard non-hormonal systemic therapy docetaxel (DTX) represents an important challenge. Cancer-associated fibroblasts (CAFs) play a crucial role in resistance to therapy because of their prevalence and functional pleiotropy in tumor environments. Our previous research revealed that MPSSS, a novel polysaccharide extracted from Lentinus edodes, could significantly attenuate the immunosuppressive function of myeloid suppressor cells and CAFs. In this study, we investigated whether MPSSS could potentiate the efficacy of DTX against prostate cancer by inhibiting CAF-induced chemoresistance and elucidated its underlying mechanisms. The sensitivity of PC-3 prostate cancer cells cultured with conditioned medium derived from CAFs (CAF-CM) to DTX was assessed. The resistance effect induced by CAF-CM was abolished when CAFs were pretreated with MPSSS. Bioinformatic analysis of datasets from the Gene Expression Omnibus database revealed the activation of the transforming growth factor β1 (TGF-β1) signaling pathway in DTX-resistant cells. Based on this finding, we demonstrated that treatment with the TGF-β1 receptor inhibitor SB525334 reversed DTX resistance in CAFs, suggesting that TGF-β1 secreted by CAFs was a crucial intermediary in the development of DTX resistance in PC3 cells. Further research revealed that MPSSS decreases the secretion of TGF-β1 by inhibiting the JAK2/STAT3 pathway via Toll-like receptor 4 in CAFs. Overall, MPSSS might be a potential adjuvant treatment for DTX resistance in prostate cancer.
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Affiliation(s)
- Wensheng Zhang
- Chinese PLA medical school, Beijing, China
- Department of Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Ning Tao
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
| | - Li Bai
- Chinese PLA medical school, Beijing, China.
- Department of Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China.
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9
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Li R, Rao JN, Smith AD, Chung HK, Xiao L, Wang JY, Turner DJ. miR-542-5p targets c-myc and negates the cell proliferation effect of SphK1 in intestinal epithelial cells. Am J Physiol Cell Physiol 2023; 324:C565-C572. [PMID: 36622069 PMCID: PMC9942902 DOI: 10.1152/ajpcell.00145.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 12/22/2022] [Accepted: 12/28/2022] [Indexed: 01/10/2023]
Abstract
Intestinal epithelial barrier defects occur commonly during a variety of pathological conditions, though their underlying mechanisms are not completely understood. Sphingosine-1-phosphate (S1P) has been shown to be a critical regulator of proliferation and of maintenance of an intact intestinal epithelial barrier, as is also sphingosine kinase 1 (SphK1), the rate-limiting enzyme for S1P synthesis. SphK1 has been shown to modulate its effect on intestinal epithelial proliferation through increased levels of c-myc. We conducted genome-wide profile analysis to search for differential microRNA expression related to overexpressed SphK1 demonstrating adjusted expression of microRNA 542-5p (miR-542-5p). Here, we show that miR-542-5p is regulated by SphK1 activity and is an effector of c-myc translation that ultimately serves as a critical regulator of the intestinal epithelial barrier. miR-542-5p directly regulates c-myc translation through direct binding to the c-myc mRNA. Exogenous S1P analogs administered in vivo protect murine intestinal barrier from damage due to mesenteric ischemia reperfusion, and damaged intestinal tissue had increased levels of miR-542-5p. These results indicate that miR-542-5p plays a critical role in the regulation of S1P-mediated intestinal barrier function, and may highlight a novel role in potential therapies.
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Affiliation(s)
- Ruiyun Li
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
- Baltimore VA Medical Center, Baltimore, Maryland
| | - Jaladanki N Rao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
- Baltimore VA Medical Center, Baltimore, Maryland
| | - Alexis D Smith
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Hee Kyoung Chung
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
- Baltimore VA Medical Center, Baltimore, Maryland
| | - Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
- Baltimore VA Medical Center, Baltimore, Maryland
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
- Baltimore VA Medical Center, Baltimore, Maryland
- Cell Biology Group, Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Douglas J Turner
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
- Baltimore VA Medical Center, Baltimore, Maryland
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10
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Donati G, Ravà M, Filipuzzi M, Nicoli P, Cassina L, Verrecchia A, Doni M, Rodighiero S, Parodi F, Boletta A, Vellano CP, Marszalek JR, Draetta GF, Amati B. Targeting mitochondrial respiration and the BCL2 family in high-grade MYC-associated B-cell lymphoma. Mol Oncol 2021; 16:1132-1152. [PMID: 34632715 PMCID: PMC8895457 DOI: 10.1002/1878-0261.13115] [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: 05/17/2021] [Revised: 08/27/2021] [Accepted: 10/08/2021] [Indexed: 01/02/2023] Open
Abstract
Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B‐cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with—and most likely a driver of—gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high‐grade MYC‐associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS‐010759. Mechanistically, IACS‐010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC‐overexpressing cells. In line with these findings, the BCL2‐inhibitory compound venetoclax synergized with IACS‐010759 against double‐hit lymphoma (DHL), a high‐grade malignancy with concurrent activation of MYC and BCL2. In BCL2‐negative lymphoma cells, instead, killing by IACS‐010759 was potentiated by the Mcl‐1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3‐mimetic drugs provides a novel therapeutic principle against aggressive, MYC‐associated DLBCL variants.
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Affiliation(s)
- Giulio Donati
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
| | - Micol Ravà
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
| | | | - Paola Nicoli
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
| | - Laura Cassina
- IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Mirko Doni
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
| | | | | | | | - Christopher P Vellano
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), Houston, TX, USA
| | - Joseph R Marszalek
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), Houston, TX, USA
| | - Giulio F Draetta
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bruno Amati
- European Institute of Oncology (IEO)-IRCCS, Milan, Italy
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11
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Prakash A, Saxena VK, Kumar R, Tomar S, Singh MK, Singh G. Differential gene expression in liver of colored broiler chicken divergently selected for residual feed intake. Trop Anim Health Prod 2021; 53:403. [PMID: 34268607 DOI: 10.1007/s11250-021-02844-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 07/02/2021] [Indexed: 10/20/2022]
Abstract
Feed constitutes about 60-70% of the total cost of poultry production. So maximizing the feed efficiency will reduce production cost. The rapid growth in the juvenile period is essential to achieve higher body weight. Therefore, identifying the genes and pathways involved in rapid growth at an early age with a lesser requirement of feed is of utmost importance to further economize the broiler production. The efficiency of feed utilization was measured using RFI (residual feed intake). The present study aimed to estimate the RFI (0-5 week) in a population of indigenously developed colored broiler sire line chicken as well as identifying the differentially expressed genes influencing RFI in high and low RFI groups. The liver samples of high and low RFI broiler chicken aged 35 days were used for microarray analysis. A total of 2798 differentially expressed genes (DEGs) were identified, out of which 913 genes were downregulated and 1885 were upregulated. The fold change varied from - 475.17 to 552.94. A subset of genes was confirmed by qRT-PCR, and outcomes were matched well with microarray data. In the functional annotation study of DEGs, the highest significant GO (Gene Ontology) terms in the biological process included protein transport, protein localization, regulation of apoptosis, and mitochondrial transport. Gene network analysis of these DEGs plays an important role to understand the interaction among genes. Study of the important genes which were differentially expressed and the related molecular pathways in this population may hold the potential for future breeding strategies for augmenting feed efficiency.
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Affiliation(s)
- A Prakash
- College of Veterinary Science, GADVASU, Rampura Phul, Bathinda, Punjab, India.
| | - V K Saxena
- Division of Avian Genetics and Breeding, Central Avian Research Institute - Indian Council of Agricultural Research, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - Ravi Kumar
- Department of Animal Biotechnology, National Institute of Animal Biotechnology, Hyderabad, 500075, Telangana, India
| | - S Tomar
- Division of Avian Genetics and Breeding, Central Avian Research Institute - Indian Council of Agricultural Research, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
| | - M K Singh
- COVS, DUVASU, Mathura, Uttar Pradesh, India
| | - Gagandeep Singh
- College of Veterinary Science, GADVASU, Rampura Phul, Bathinda, Punjab, India
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12
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Rajput PS, Khan SR, Singh P, Chawla PA. Treatment of Small Cell Lung Cancer with Lurbinectedin: A Review. Anticancer Agents Med Chem 2021; 22:812-820. [PMID: 34229593 DOI: 10.2174/1871520621666210706150057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 05/15/2021] [Accepted: 05/23/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Lurbinectedin was approved on June 15, 2020 by Food and Drug Administration with a brand name ZEPZELCA as the first systematic approved therapy for patients having Small Cell Lung Cancer (SCLC). OBJECTIVES In this review, an attempt is made to summarize different aspects of Lurbinectedin, including the pathophysiology, chemistry, chemical synthesis, mechanism of action, adverse reactions, including pharmacokinetics of lurbinectedin. Special attention is given to various reported clinical trials of lurbinectedin. METHODS A comprehensive literature search was conducted in the relevant databases like ScienceDirect, PubMed, ResearchGate and Google Scholar to identify studies. Further upon a thorough study of these reports, significant findings/data were collected and compiled under suitable headings. Important findings related to clinical trials have been tabulated. CONCLUSION Lurbinectedin is known to act by inhibiting the active transcription of encoding genes, thereby bringing about the suppression of tumour related macrophages with an impact on tumour atmosphere. Lurbinectedin has emerged as a potential drug candidate for the treatment of small cell lung cancer (SCLC).
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Affiliation(s)
- Prince Singh Rajput
- Department of Pharmaceutical Analysis, ISF College of Pharmacy, G.T. Road, Moga-142 001, Punjab, India
| | - Sharib Raza Khan
- Department of Pharmaceutical Analysis, ISF College of Pharmacy, G.T. Road, Moga-142 001, Punjab, India
| | - Preeti Singh
- Department of Pharmaceutical Analysis, ISF College of Pharmacy, G.T. Road, Moga-142 001, Punjab, India
| | - Pooja A Chawla
- Department of Pharmaceutical Analysis, ISF College of Pharmacy, G.T. Road, Moga-142 001, Punjab, India
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13
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Lu Y, Yang Q, Su Y, Ji Y, Li G, Yang X, Xu L, Lu Z, Dong J, Wu Y, Bei JX, Pan C, Gu X, Li B. MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma. Cell Death Dis 2021; 12:511. [PMID: 34011924 PMCID: PMC8134466 DOI: 10.1038/s41419-021-03790-w] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/29/2021] [Accepted: 04/29/2021] [Indexed: 01/01/2023]
Abstract
MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(-) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.
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Affiliation(s)
- Yuxiong Lu
- Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qing Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yubin Su
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yin Ji
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Simcere Diagnostics Co., Ltd., Nanjing, China
| | - Guobang Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xianzhi Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Liyan Xu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhaoliang Lu
- Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jiajun Dong
- Department of Neurosurgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital, Sun Yat-sen University, Jiangmen, China
| | - Yi Wu
- Department of Neurosurgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital, Sun Yat-sen University, Jiangmen, China
| | - Jin-Xin Bei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Center for Precision Medicine, Sun Yat-sen University, Guangzhou, China
| | - Chaoyun Pan
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoqiong Gu
- Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Bo Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Center for Precision Medicine, Sun Yat-sen University, Guangzhou, China
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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14
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Fairlie WD, Lee EF. Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer. Int J Mol Sci 2021; 22:2841. [PMID: 33799592 PMCID: PMC8000576 DOI: 10.3390/ijms22062841] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/30/2022] Open
Abstract
B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature can be attributed to both proteins playing essential roles in the normal functioning of a cell, and by extension a whole organism, but also due to their central role in disease, most notably, cancer. Many cancers arise due to genetic lesions resulting in deregulation of both proteins, and indeed the development and survival of tumours is often dependent on co-operativity between these protein families. In this review we will discuss the individual roles of both proteins in cancer, describe cancers where co-operativity between them has been well-characterised and finally, some strategies to target these proteins therapeutically.
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Affiliation(s)
- Walter Douglas Fairlie
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3084, Australia
| | - Erinna F. Lee
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3084, Australia
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15
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Kong IY, Rimes JS, Light A, Todorovski I, Jones S, Morand E, Knight DA, Bergman YE, Hogg SJ, Falk H, Monahan BJ, Stupple PA, Street IP, Heinzel S, Bouillet P, Johnstone RW, Hodgkin PD, Vervoort SJ, Hawkins ED. Temporal Analysis of Brd4 Displacement in the Control of B Cell Survival, Proliferation, and Differentiation. Cell Rep 2020; 33:108290. [PMID: 33086063 DOI: 10.1016/j.celrep.2020.108290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 05/24/2020] [Accepted: 09/29/2020] [Indexed: 12/16/2022] Open
Abstract
JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism that JQ1 targets to elicit changes in antibody production is not understood. Our results show that JQ1 induces apoptosis, reduces cell proliferation, and as a consequence, inhibits antibody-secreting cell differentiation. ChIP-sequencing reveals a selective displacement of Brd4 in response to acute JQ1 treatment (<2 h), resulting in specific transcriptional repression. After 8 h, subsequent alterations in gene expression arise as a result of the global loss of Brd4 occupancy. We demonstrate that apoptosis induced by JQ1 is solely attributed to the pro-apoptotic protein Bim (Bcl2l11). Conversely, cell-cycle regulation by JQ1 is associated with multiple Myc-associated gene targets. Our results demonstrate that JQ1 drives temporal changes in Brd4 displacement that results in a specific transcriptional profile that directly affects B cell survival and proliferation to modulate the humoral immune response.
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Affiliation(s)
- Isabella Y Kong
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Joel S Rimes
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Amanda Light
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Izabela Todorovski
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - Sarah Jones
- Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Eric Morand
- Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Deborah A Knight
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - Ylva E Bergman
- Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Simon J Hogg
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - Hendrik Falk
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia
| | - Brendon J Monahan
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia
| | - Paul A Stupple
- Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Ian P Street
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx), Melbourne, VIC 3000, Australia
| | - Susanne Heinzel
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Philippe Bouillet
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Ricky W Johnstone
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - Philip D Hodgkin
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Stephin J Vervoort
- Cancer Therapeutics and Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
| | - Edwin D Hawkins
- Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
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16
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Drug-like biimidazole derivatives dually target c-MYC/BCL-2 G-quadruplexes and inhibit acute myeloid leukemia. Bioorg Chem 2020; 104:104264. [PMID: 32920366 DOI: 10.1016/j.bioorg.2020.104264] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/27/2020] [Accepted: 08/27/2020] [Indexed: 01/29/2023]
Abstract
Chemotherapy is the main approach for treating acute myeloid leukemia (AML). However, this therapy can cause severe side effects as well as drug resistance, hence calling for new therapeutic strategies. As c-MYC and BCL-2 are often overexpressed in AML, and synergism between c-MYC and BCL-2 promotes tumorigenesis, therefore, dual targeting of c-MYC/BCL-2 promoter G-quadruplexes (G4s) and then inhibiting the targeted gene expression would be a potential strategy in ALM treatment. In this work, in the search of dual ligands, we performed a screening assay with an in-house, imidazole-based compound library. Consequently, two drug-like biimidazole derivatives were identified as selective c-MYC/BCL-2 G4 binders, of which, BIM-2 was selected as the candidate for inhibiting AML cell growth. Then, BIM-2 was demonstrated to downregulate both c-MYC and BCL-2 expression, and thereby cause cell cycle arrest at G0/G1 phase and apoptosis in AML cells. Furthermore, the possible end-stacking binding modes between BIM-2 and c-MYC/BCL-2 G4s were revealed by NMR and molecular docking studies. Accordingly, this study provides a new class of drug-like dual-selective c-MYC/BCL-2 G4 ligands for the potential treatment of AML.
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17
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Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol 2020; 21:678-695. [PMID: 32873928 DOI: 10.1038/s41580-020-0270-8] [Citation(s) in RCA: 606] [Impact Index Per Article: 121.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 12/17/2022]
Abstract
The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.
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Shahar N, Larisch S. Inhibiting the inhibitors: Targeting anti-apoptotic proteins in cancer and therapy resistance. Drug Resist Updat 2020; 52:100712. [DOI: 10.1016/j.drup.2020.100712] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/29/2020] [Accepted: 06/05/2020] [Indexed: 12/14/2022]
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Strasser A, Vaux DL. Cell Death in the Origin and Treatment of Cancer. Mol Cell 2020; 78:1045-1054. [PMID: 32516599 DOI: 10.1016/j.molcel.2020.05.014] [Citation(s) in RCA: 235] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/12/2020] [Accepted: 05/12/2020] [Indexed: 12/11/2022]
Abstract
Cell death, or, more specifically, cell suicide, is a process of fundamental importance to human health. Throughout our lives, over a million cells are produced every second. When organismal growth has stopped, to balance cell division, a similar number of cells must be removed. This is achieved by activation of molecular mechanisms that have evolved so that cells can destroy themselves. The first clues regarding the nature of one of these mechanisms came from studying genes associated with cancer, in particular the gene for BCL-2. Subsequent studies revealed that mutations or other defects that inhibit cell death allow cells to accumulate, prevent removal of cells with damaged DNA, and increase the resistance of malignant cells to chemotherapy. Knowledge of this mechanism has allowed development of drugs that kill cancer cells by directly activating the cell death machinery and by synergizing with conventional chemotherapy as well as targeted agents to achieve improved outcomes for cancer patients.
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Affiliation(s)
- Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
| | - David L Vaux
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
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20
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Virdis P, Migheli R, Galleri G, Fancello S, Cadoni MPL, Pintore G, Petretto GL, Marchesi I, Fiorentino FP, di Francesco A, Sanges F, Bagella L, Muroni MR, Fozza C, De Miglio MR, Podda L. Antiproliferative and proapoptotic effects of Inula viscosa extract on Burkitt lymphoma cell line. Tumour Biol 2020; 42:1010428319901061. [PMID: 32013807 DOI: 10.1177/1010428319901061] [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] [Indexed: 12/21/2022] Open
Abstract
Burkitt lymphoma is a very aggressive B-cell non-Hodgkin lymphoma. Although remarkable progress has been made in the therapeutic scenario for patients with Burkitt lymphoma, search and development of new effective anticancer agents to improve patient outcome and minimize toxicity has become an urgent issue. In this study, the antitumoral activity of Inula viscosa, a traditional herb obtained from plants collected on the Asinara Island, Italy, was evaluated in order to explore potential antineoplastic effects of its metabolites on Burkitt lymphoma. Raji human cell line was treated with increasing Inula viscosa extract concentration for cytotoxicity screening and subsequent establishment of cell cycle arrest and apoptosis. Moreover, gene expression profiles were performed to identify molecular mechanisms involved in the anticancer activities of this medical plant. The Inula viscosa extract exhibited powerful antiproliferative and cytotoxic activities on Raji cell line, showing a dose- and time-dependent decrease in cell viability, obtained by cell cycle arrest in the G2/M phase and an increase in cell apoptosis. The treatment with Inula viscosa caused downregulation of genes involved in cell cycle and proliferation (c-MYC, CCND1) and inhibition of cell apoptosis (BCL2, BCL2L1, BCL11A). The Inula viscosa extract causes strong anticancer effects on Burkitt lymphoma cell line. The molecular mechanisms underlying such antineoplastic activity are based on targeting and downregulation of genes involved in cell cycle and apoptosis. Our data suggest that Inula viscosa natural metabolites should be further exploited as potential antineoplastic agents against Burkitt lymphoma.
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Affiliation(s)
- Patrizia Virdis
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Rossana Migheli
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Grazia Galleri
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Silvia Fancello
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Maria Piera L Cadoni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Giorgio Pintore
- Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy
| | | | - Irene Marchesi
- Kitos Biotech Srls, Porto Conte Ricerche, Sassari, Italy
| | - Francesco Paolo Fiorentino
- Kitos Biotech Srls, Porto Conte Ricerche, Sassari, Italy.,Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Alessandra di Francesco
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Francesca Sanges
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Luigi Bagella
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Maria Rosaria Muroni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Claudio Fozza
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Maria Rosaria De Miglio
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Luigi Podda
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
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21
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Bisso A, Sabò A, Amati B. MYC in Germinal Center-derived lymphomas: Mechanisms and therapeutic opportunities. Immunol Rev 2019; 288:178-197. [PMID: 30874346 DOI: 10.1111/imr.12734] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/11/2018] [Indexed: 12/13/2022]
Abstract
The rearrangement of immunoglobulin loci during the germinal center reaction is associated with an increased risk of chromosomal translocations that activate oncogenes such as MYC, BCL2 or BCL6, thus contributing to the development of B-cell lymphomas. MYC and BCL2 activation are initiating events in Burkitt's (BL) and Follicular Lymphoma (FL), respectively, but can occur at later stages in other subtypes such as Diffuse Large-B Cell Lymphoma (DLBCL). MYC can also be activated during the progression of FL to the transformed stage. Thus, either DLBCL or FL can give rise to aggressive double-hit lymphomas (DHL) with concurrent activation of MYC and BCL2. Research over the last three decades has improved our understanding of the functions of these oncogenes and the basis for their cooperative action in lymphomagenesis. MYC, in particular, is a transcription factor that contributes to cell activation, growth and proliferation, while concomitantly sensitizing cells to apoptosis, the latter being blocked by BCL2. Here, we review our current knowledge about the role of MYC in germinal center B-cells and lymphomas, discuss MYC-induced dependencies that can sensitize cancer cells to select pharmacological inhibitors, and illustrate their therapeutic potential in aggressive lymphomas-and in particular in DHL, in combination with BCL2 inhibitors.
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Affiliation(s)
- Andrea Bisso
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Arianna Sabò
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Bruno Amati
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
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22
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Abstract
Apoptosis is a highly conserved programme for removing damaged and unwanted cells. Apoptosis in most cells is coordinated on mitochondria by the Bcl-2 family of proteins. The balance between pro- and anti-apoptotic Bcl-2 family proteins sets a threshold for mitochondrial apoptosis, a balance that is altered during cancer progression. Consequently, avoidance of cell death is an established cancer hallmark. Although there is a general perception that tumour cells are more resistant to apoptosis than their normal counterparts, the realities of cell death regulation in cancer are more nuanced. In this review we discuss how a profound understanding of this control has led to new therapeutic approaches, including the new class of BH3-mimetics, which directly target apoptosis as a vulnerability in cancer. We discuss recent findings that highlight the current limitations in our understanding of apoptosis and how these novel therapeutics work.
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Affiliation(s)
- Andrew Gilmore
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Louise King
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
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23
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Hartung F, Patil A, Meshram RJ, Weber GF. Gene expression signatures of site-specificity in cancer metastases. Clin Exp Metastasis 2019; 37:159-171. [PMID: 31555944 DOI: 10.1007/s10585-019-09995-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 09/19/2019] [Indexed: 11/26/2022]
Abstract
We have previously shown that metastases are generally characterized by a core program of gene expression that induces the oxidative energy metabolism, activates vascularization/tissue remodeling, silences extracellular matrix interactions, and alters ion homeostasis. This core program distinguishes metastases from their originating primary tumors as well as from their target host tissues. We hypothesized that organ preference is reflected in additional, site-selective components within the metastatic gene expression programs. Expanding our prior analysis of 653 human gene expression profiles plus data from a murine model, we find that the release from the primary tumor is associated with a suppression of functions that are important for the identity of the organ of origin, such as a down-regulation of steroid hormone responsiveness in the disseminated foci derived from prostate cancer. Metastases adjust to their target microenvironment by up-regulating-even overexpressing-genes and genetic programs that are characteristic of that organ. Finally, alterations in RNA and protein processing as well as immune deviation are common. In the clinic, metastases are mostly treated with the chemotherapy protocols devised for their primary tumors. Adjustments that account for the gene expression differences between primary and metastatic cancers have the potential to improve the currently dismal success rates.
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Affiliation(s)
- Franz Hartung
- University of Cincinnati Academic Health Center, Cincinnati, OH, USA
| | - Aditya Patil
- Bioinformatics Centre, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Rohan J Meshram
- Bioinformatics Centre, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Georg F Weber
- University of Cincinnati Academic Health Center, Cincinnati, OH, USA.
- James L. Winkle College of Pharmacy, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0514, USA.
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24
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Zhou P, Chen X, Li M, Sun X, Tan J, Wang X, Chu Y, Zhang Y, Cheng T, Zhou J, Wang G, Yuan W. Overexpression of PRDM5 promotes acute myeloid leukemia cell proliferation and migration by activating the JNK pathway. Cancer Med 2019; 8:3905-3917. [PMID: 31119897 PMCID: PMC6639193 DOI: 10.1002/cam4.2261] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 12/24/2022] Open
Abstract
PRDM family proteins are dysregulated in many human diseases, especially hematological malignancies and solid cancers, and share a unique N‐terminal PR domain followed by zinc fingers toward the C terminus. With a high frequency of DNA promoter hypermethylation, PRDM5 is primarily considered as a tumor suppressor in solid tumors. However, little is known about the function of PRDM5 in blood malignancies, especially acute myeloid leukemia (AML). In this study, we showed that high PRDM5 expression levels were independently correlated with poor overall survival in AML patients. PRDM5 overexpression promoted cell proliferation, colony formation, and migration in vitro and enhanced tumorigenesis in an in vivo xenograft model. Furthermore, we found that PRDM5 overexpression promoted cell cycle progression with the decreased level of cell cycle inhibitors such as p16 and p21, and regulated the expression of epithelial‐mesenchymal transition markers ZO‐1 and Vimentin to promote migration. Moreover, we observed that PRDM5 upregulated the Jun N‐terminal kinase (JNK) signaling pathway and downregulated c‐Myc expression. Pharmacological inhibition of JNK by SP600125 partially abrogated PRDM5‐induced cell proliferation and migration. Taken together, our findings demonstrate that PRDM5 functions as an oncogenic driver in AML via JNK pathway, suggesting that PRDM5 is a potential therapeutic target for AML.
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Affiliation(s)
- Pan Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xing Chen
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengke Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Xiaolu Sun
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Jiaqi Tan
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaomin Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Yajing Chu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Yicheng Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Jianfeng Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Gaoxiang Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Weiping Yuan
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
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25
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BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis 2019; 10:177. [PMID: 30792387 PMCID: PMC6384907 DOI: 10.1038/s41419-019-1407-6] [Citation(s) in RCA: 458] [Impact Index Per Article: 76.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 12/17/2018] [Accepted: 01/29/2019] [Indexed: 12/17/2022]
Abstract
The BCl-2 family has long been identified for its role in apoptosis. Following the initial discovery of BCL-2 in the context of B-cell lymphoma in the 1980s, a number of homologous proteins have since been identified. The members of the Bcl-2 family are designated as such due to their BCL-2 homology (BH) domains and involvement in apoptosis regulation. The BH domains facilitate the family members’ interactions with each other and can indicate pro- or anti-apoptotic function. Traditionally, these proteins are categorised into one of the three subfamilies; anti-apoptotic, BH3-only (pro-apoptotic), and pore-forming or ‘executioner’ (pro-apoptotic) proteins. Each of the BH3-only or anti-apoptotic proteins has a distinct pattern of activation, localisation and response to cell death or survival stimuli. All of these can vary across cell or stress types, or developmental stage, and this can cause the delineation of the roles of BCL-2 family members. Added to this complexity is the presence of relatively uncharacterised isoforms of many of the BCL-2 family members. There is a gap in our knowledge regarding the function of BCL-2 family isoforms. BH domain status is not always predictive or indicative of protein function, and several other important sequences, which can contribute to apoptotic activity have been identified. While therapeutic strategies targeting the BCL-2 family are constantly under development, it is imperative that we understand the molecules, which we are attempting to target. This review, discusses our current knowledge of anti-apoptotic BCL-2 family isoforms. With significant improvements in the potential for splicing therapies, it is important that we begin to understand the distinctions of the BCL-2 family, not limited to just the mechanisms of apoptosis control, but in their roles outside of apoptosis.
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26
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Chen G, Liu C, Meng G, Zhang C, Chen F, Tang S, Hong H, Zhang C. Neuroprotective effect of mogrol against Aβ 1-42 -induced memory impairment neuroinflammation and apoptosis in mice. ACTA ACUST UNITED AC 2018; 71:869-877. [PMID: 30585314 DOI: 10.1111/jphp.13056] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Accepted: 11/18/2018] [Indexed: 01/07/2023]
Abstract
OBJECTIVES Cognitive impairment is the main character of Alzheimer's disease (AD). This study mainly focused on whether mogrol, a tetracyclic triterpenoids compound of Siraitia grosvenorii Swingle, can ameliorate the memory impairment induced by Aβ1-42 . METHODS Memory impairment mice model was made by stereotactic intra-hippocampal microinjection of Aβ1-42 (410 pm/mouse). Mogrol (20, 40, 80 mg/kg) was given to mice by intragastric administration at 3 days after Aβ1-42 injection for totally 3 weeks. Morris water maze test and Y-maze test were operated to evaluate the therapeutic effect of morgrol on Aβ1-42 -induced memory impairments. Immunohistochemical analyses and Hoechst 33258 assay were used to evaluate effect of morgrol on Aβ1-42 -induced microglia overactivation and apoptotic response in hippocampus of mice. Western blotting assay was used to evaluate effect of mogrol on the Aβ1-42 -activated NF-κB signaling. KEY FINDINGS Mogrol could significantly alleviate Aβ1-42 -induced memory impairments, inhibit Aβ1-42 -induced microglia overactivation and prevent Aβ1-42 -triggered apoptotic response in the hippocampus. Mogrol also could suppress Aβ1-42 -activated NF-κB signaling, reduce the production of proinflammatory cytokines. CONCLUSIONS This study suggested that mogrol would ameliorate the memory impairment induced by Aβ1-42 , which is involved in anti-inflammation and anti-apoptosis in the brain.
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Affiliation(s)
- Gangling Chen
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Caihong Liu
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Guoliang Meng
- School of Pharmacy, Nantong University, Nantong, China
| | - Chunteng Zhang
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Fang Chen
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Susu Tang
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Hao Hong
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Chaofeng Zhang
- State Key Laboratory of Natural Medicines, Research Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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27
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Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth. Nat Cell Biol 2018; 20:1256-1266. [PMID: 30361695 PMCID: PMC6291208 DOI: 10.1038/s41556-018-0218-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 09/18/2018] [Indexed: 12/28/2022]
Abstract
Oncogenic lesions are surprisingly common in morphologically and functionally normal human skin, however, the cellular and molecular mechanisms that suppress their cancer-driving potential to maintain tissue homeostasis are unknown. By employing assays for direct and quantitative assessment of cell fate choices in vivo, we show that oncogenic activation of PI3K/AKT, the most commonly activated oncogenic pathway in cancer, promotes differentiation and cell-cycle exit of epidermal progenitors. As a result, oncogenic PI3K/AKT activated epidermis exhibits growth disadvantage even though its cells are more proliferative. To uncover the underlying mechanism behind oncogene-induced differentiation, we conduct a series of genetic screens in vivo, and identify an AKT substrate SH3RF1 as a specific promoter of epidermal differentiation that has no effect on proliferation. Our study provides evidence for a direct, cell autonomous mechanism that can suppresses progenitor cell renewal and block clonal expansion of epidermal cells bearing a common and activating mutation in Pik3ca.
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28
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Wang H, Liu B, Yin X, Guo L, Jiang W, Bi H, Guo D. Excessive zinc chloride induces murine photoreceptor cell death via reactive oxygen species and mitochondrial signaling pathway. J Inorg Biochem 2018; 187:25-32. [DOI: 10.1016/j.jinorgbio.2018.07.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 07/02/2018] [Accepted: 07/17/2018] [Indexed: 01/04/2023]
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29
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Campbell KJ, Tait SWG. Targeting BCL-2 regulated apoptosis in cancer. Open Biol 2018; 8:rsob.180002. [PMID: 29769323 PMCID: PMC5990650 DOI: 10.1098/rsob.180002] [Citation(s) in RCA: 358] [Impact Index Per Article: 51.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 04/09/2018] [Indexed: 12/23/2022] Open
Abstract
The ability of a cell to undergo mitochondrial apoptosis is governed by pro- and anti-apoptotic members of the BCL-2 protein family. The equilibrium of pro- versus anti-apoptotic BCL-2 proteins ensures appropriate regulation of programmed cell death during development and maintains organismal health. When unbalanced, the BCL-2 family can act as a barrier to apoptosis and facilitate tumour development and resistance to cancer therapy. Here we discuss the BCL-2 family, their deregulation in cancer and recent pharmaceutical developments to target specific members of this family as cancer therapy.
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Affiliation(s)
- Kirsteen J Campbell
- Cancer Research UK Beatson Institute, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
| | - Stephen W G Tait
- Cancer Research UK Beatson Institute, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
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30
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Hu J, Han Q, Gu Y, Ma J, McGrath M, Qiao F, Chen B, Song C, Ge Z. Circular RNA PVT1 expression and its roles in acute lymphoblastic leukemia. Epigenomics 2018; 10:723-732. [PMID: 29693417 DOI: 10.2217/epi-2017-0142] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM The roles of circular RNA PVT1 (circPVT1) are explored in the patients with acute lymphoblastic leukemia (ALL). METHODS The circPVT1 level was detected by qRT-PCR and western blot. The apoptotic cells were examined by the annexin V assay in lentiviral shRNA knockdown cells. RESULTS circPVT1 was highly expressed in ALL compared with normal bone marrow samples. circPVT1 expression was also significantly higher in ALL cell lines. circPVT1 knockdown inhibited cell proliferation and induced cell apoptosis through suppression of its neighbor gene c-Myc, and antiapoptotic Bcl-2 protein expression. CONCLUSION circPVT1 is upregulated in ALL. Silencing circPVT1 results in cell growth arrest and apoptosis of the cells. Our results also suggested a therapeutic potential of targeting circPVT1 in ALL.
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Affiliation(s)
- Jiaojiao Hu
- Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Qi Han
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - Yan Gu
- Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Jinlong Ma
- Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Mary McGrath
- Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA
| | - Fengchang Qiao
- Department of Prenatal Diagnosis, State Key Laboratory of Reproductive Medicine, Obstetrics & Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing 210004, China
| | - Baoan Chen
- Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Chunhua Song
- Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA
| | - Zheng Ge
- Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
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31
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Ravà M, D’Andrea A, Nicoli P, Gritti I, Donati G, Doni M, Giorgio M, Olivero D, Amati B. Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma. Sci Transl Med 2018; 10:10/426/eaan8723. [DOI: 10.1126/scitranslmed.aan8723] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/08/2017] [Accepted: 12/28/2017] [Indexed: 01/10/2023]
Abstract
High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. MYC activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of MYC-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. BCL2 activation in mouse Eμ-myc lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human MYC/BCL2 DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.
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BCL-2 and PAX2 Expressions in EIN which Had Been Previously Diagnosed as Non-Atypical Hyperplasia. Pathol Oncol Res 2017; 25:471-476. [DOI: 10.1007/s12253-017-0378-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 12/15/2017] [Indexed: 11/27/2022]
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Leverson JD, Sampath D, Souers AJ, Rosenberg SH, Fairbrother WJ, Amiot M, Konopleva M, Letai A. Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax. Cancer Discov 2017; 7:1376-1393. [PMID: 29146569 PMCID: PMC5728441 DOI: 10.1158/2159-8290.cd-17-0797] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 10/12/2017] [Accepted: 10/19/2017] [Indexed: 12/12/2022]
Abstract
Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax.Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1376-93. ©2017 AACR.
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Affiliation(s)
| | | | | | | | | | - Martine Amiot
- CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France
| | - Marina Konopleva
- The University of Texas MD Anderson Cancer Center, Houston, Texas
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Campbell KJ, Vandenberg CJ, Anstee NS, Hurlin PJ, Cory S. Mnt modulates Myc-driven lymphomagenesis. Cell Death Differ 2017; 24:2117-2126. [PMID: 28800127 PMCID: PMC5686348 DOI: 10.1038/cdd.2017.131] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/06/2017] [Indexed: 12/27/2022] Open
Abstract
The transcriptional represser Mnt is a functional antagonist of the proto-oncoprotein Myc. Both Mnt and Myc utilise Max as an obligate partner for DNA binding, and Myc/Max and Mnt/Max complexes compete for occupancy at E-box DNA sequences in promoter regions. We have previously shown in transgenic mouse models that the phenotype and kinetics of onset of haemopoietic tumours varies with the level of Myc expression. We reasoned that a decrease in the level of Mnt would increase the functional level of Myc and accelerate Myc-driven tumorigenesis. We tested the impact of reduced Mnt in three models of myc transgenic mice and in p53+/- mice. To our surprise, mnt heterozygosity actually slowed Myc-driven tumorigenesis in vavP-MYC10 and Eμ-myc mice, suggesting that Mnt facilitates Myc-driven oncogenesis. To explore the underlying cause of the delay in tumour development, we enumerated Myc-driven cell populations in healthy young vavP-MYC10 and Eμ-myc mice, expecting that the reduced rate of leukaemogenesis in mnt heterozygous mice would be reflected in a reduced number of preleukaemic cells, due to increased apoptosis or reduced proliferation or both. However, no differences were apparent. Furthermore, when mnt+/+ and mnt+/- pre-B cells from healthy young Eμ-myc mice were compared in vitro, no differences were seen in their sensitivity to apoptosis or in cell size or cell cycling. Moreover, the frequencies of apoptotic, senescent and proliferating cells were comparable in vivo in mnt+/- and mnt+/+ Eμ-myc lymphomas. Thus, although mnt heterozygosity clearly slowed lymphomagenesis in vavP-MYC10 and Eμ-myc mice, the change(s) in cellular properties responsible for this effect remain to be identified.
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Affiliation(s)
- Kirsteen J Campbell
- Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC 3052, Australia
| | - Cassandra J Vandenberg
- Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Natasha S Anstee
- Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | | | - Suzanne Cory
- Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
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MicroRNA-21 inhibits mitochondria-mediated apoptosis in keloid. Oncotarget 2017; 8:92914-92925. [PMID: 29190966 PMCID: PMC5696232 DOI: 10.18632/oncotarget.21656] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/28/2017] [Indexed: 12/21/2022] Open
Abstract
MicroRNA-21 acts as an oncogene by promoting cell proliferation and migration, whereas inhibiting apoptosis in majority of cancers. MicroRNA-21 is upregulated in human keloid fibroblasts. We hypothesized that microRNA-21 may contribute to pathogenesis of keloid fibroblasts. First, enhanced miR-21 but reduced mitochondrial-mediated apoptosis observed in keloid tissues indicated its importance in keloids development. Second, upregulation of microRNA-21 induced a decrease in the ratio of BAX to BCL-2 and suppressed mitochondrial fission in keloid fibroblasts. Third, by attenuating the decline in cellular mitochondrial membrane potential, overexpression of miR-21 suppressed cytochrome c release to the cytoplasm, followed by a decrease in the activity of intracellular caspase-9 and caspase-3, suggesting that mitochondrial-mediated proapoptotic pathway was impaired. Simultaneously, intracellular reactive oxygen species were decreased, indicating microRNA-21 undermined oxidative stress. This phenotype was reversed by miR-21 inhibition. Therefore, our study demonstrates that inhibition of microRNA-21 induces mitochondrial-mediated apoptosis in keloid fibroblasts, proposing microRNA-21 as a potential therapeutic target in keloid fibroblasts.
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Baruah PS, Beauchemin M, Parker JA, Bertrand R. Expression of human Bcl-xL (Ser49) and (Ser62) mutants in Caenorhabditis elegans causes germline defects and aneuploidy. PLoS One 2017; 12:e0177413. [PMID: 28481930 PMCID: PMC5421811 DOI: 10.1371/journal.pone.0177413] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 04/26/2017] [Indexed: 11/18/2022] Open
Abstract
An interesting feature of Bcl-xL protein is the presence of an unstructured loop domain between α1 and α2 helices, a domain not essential for its anti-apoptotic function and absent in CED-9 protein. Within this domain, Bcl-xL undergoes dynamic phosphorylation and dephosphorylation at Ser49 and Ser62 during G2 and mitosis in human cells. Studies have revealed that when these residues are mutated, cells harbour mitotic defects, including chromosome mis-attachment, lagging, bridging and mis-segregation with, ultimately, chromosome instability and aneuploidy. We undertook genetic experiments in Caenorhabditis elegans to understand the importance of Bcl-xL (Ser49) and (Ser62) in vivo. Transgenic worms carrying single-site S49A, S62A, S49D, S62D and dual site S49/62A mutants were generated and their effects were analyzed in germlines of young adult worms. Worms expressing Bcl-xL variants showed decreased egg-laying and hatching potency, variations in the length of their mitotic regions but not of their transition zones, appearance of chromosomal abnormalities at their diplotene stages, and increased germline apoptosis, with the exception of the S62D variants. Some of these transgenic strains, particularly the Ser to Ala variants, also showed slight modulations of lifespan compared to their controls. In addition, RNAi experiments silencing expression of the various Bcl-xL variants reversed their effects in vivo. Our in vivo observations confirmed the importance of Ser49 and Ser62 within Bcl-xL loop domain in maintaining chromosome stability.
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Affiliation(s)
- Prasamit Saurav Baruah
- Centre de recherche, Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal (Québec) Canada
- Institut du cancer de Montréal, Montréal (Québec) Canada
| | - Myriam Beauchemin
- Centre de recherche, Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal (Québec) Canada
- Institut du cancer de Montréal, Montréal (Québec) Canada
| | - J. Alexander Parker
- Centre de recherche, Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal (Québec) Canada
- Département de neurosciences, Université de Montréal, Montréal (Québec) Canada
| | - Richard Bertrand
- Centre de recherche, Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal (Québec) Canada
- Institut du cancer de Montréal, Montréal (Québec) Canada
- Département de médecine et Spec. médicales, Université de Montréal, Montréal (Québec) Canada
- * E-mail:
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Chen L, Yang J, Xing Z, Yuan F, Shu Y, Zhang Y, Kong X, Huang T, Li H, Cai YD. An integrated method for the identification of novel genes related to oral cancer. PLoS One 2017; 12:e0175185. [PMID: 28384236 PMCID: PMC5383255 DOI: 10.1371/journal.pone.0175185] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/21/2017] [Indexed: 12/18/2022] Open
Abstract
Cancer is a significant public health problem worldwide. Complete identification of genes related to one type of cancer facilitates earlier diagnosis and effective treatments. In this study, two widely used algorithms, the random walk with restart algorithm and the shortest path algorithm, were adopted to construct two parameterized computational methods, namely, an RWR-based method and an SP-based method; based on these methods, an integrated method was constructed for identifying novel disease genes. To validate the utility of the integrated method, data for oral cancer were used, on which the RWR-based and SP-based methods were trained, thereby building two optimal methods. The integrated method combining these optimal methods was further adopted to identify the novel genes of oral cancer. As a result, 85 novel genes were inferred, among which eleven genes (e.g., MYD88, FGFR2, NF-κBIA) were identified by both the RWR-based and SP-based methods, 70 genes (e.g., BMP4, IFNG, KITLG) were discovered only by the RWR-based method and four genes (L1R1, MCM6, NOG and CXCR3) were predicted only by the SP-based method. Extensive analyses indicate that several novel genes have strong associations with cancers, indicating the effectiveness of the integrated method for identifying disease genes.
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Affiliation(s)
- Lei Chen
- School of Life Sciences, Shanghai University, Shanghai, People’s Republic of China
- College of Information Engineering, Shanghai Maritime University, Shanghai, People’s Republic of China
| | - Jing Yang
- School of Life Sciences, Shanghai University, Shanghai, People’s Republic of China
| | - Zhihao Xing
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Fei Yuan
- Department of Science & Technology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China
| | - Yang Shu
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - YunHua Zhang
- School of Resources and Environment, Anhui Agricultural University, Hefei, Anhui, People’s Republic of China
| | - XiangYin Kong
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Tao Huang
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China
- * E-mail: (TH); (HPL); (YDC)
| | - HaiPeng Li
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China
- * E-mail: (TH); (HPL); (YDC)
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, People’s Republic of China
- * E-mail: (TH); (HPL); (YDC)
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Abstract
How can we treat cancer more effectively? Traditionally, tumours from the same anatomical site are treated as one tumour entity. This concept has been challenged by recent breakthroughs in cancer genomics and translational research that have enabled molecular tumour profiling. The identification and validation of cancer drivers that are shared between different tumour types, spurred the new paradigm to target driver pathways across anatomical sites by off-label drug use, or within so-called basket or umbrella trials which are designed to test whether molecular alterations in one tumour entity can be extrapolated to all others. However, recent clinical and preclinical studies suggest that there are tissue- and cell type-specific differences in tumorigenesis and the organization of oncogenic signalling pathways. In this Opinion article, we focus on the molecular, cellular, systemic and environmental determinants of organ-specific tumorigenesis and the mechanisms of context-specific oncogenic signalling outputs. Investigation, recognition and in-depth biological understanding of these differences will be vital for the design of next-generation clinical trials and the implementation of molecularly guided cancer therapies in the future.
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Affiliation(s)
- Günter Schneider
- Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Marc Schmidt-Supprian
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany
| | - Roland Rad
- Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Dieter Saur
- Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Chen X, Zhang X, Xue L, Hao C, Liao W, Wan Q. Treatment with Enriched Environment Reduces Neuronal Apoptosis in the Periinfarct Cortex after Cerebral Ischemia/Reperfusion Injury. Cell Physiol Biochem 2017; 41:1445-1456. [DOI: 10.1159/000468368] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 01/17/2017] [Indexed: 01/07/2023] Open
Abstract
Background/Aims: Enriched environment (EE) has been reported to exert neuroprotective effect in animal models of ischemic stroke. However, the underlying mechanism remains unclear. The purpose of this study was to investigate the effect of EE treatment on neuronal apoptosis in the periinfarct cortex after cerebral ischemia/reperfusion (I/R) injury. Methods: The cerebral I/R injury was established by middle cerebral artery occlusion (MCAO). A set of behavioral tests including the modified neurological severity score (mNSS), limb-placing test and foot-fault test were conducted. The infarct volume and the neuronal survival rate were evaluated by Nissl staining. The morphology and ultrastructure of ischemic neurons was examined by transmission electron microscopy. Neuronal apoptosis was assessed by double labeling of TdT-mediated dUTP-biotin nick end labeling (TUNEL) with NeuN. The expressions of apoptosis-related proteins were tested by western blotting and immunohistochemical labeling. Results: EE treatment improved neurological function, reduced infarct volume, increased neuronal survival rate and alleviated the morphological and ultrastructural damage of neurons (especially mitochondria) after I/R injury. EE treatment reduced the neuronal apoptosis, increased B cell lymphoma/leukemia-2 (Bcl-2) protein levels while decreased Bcl-2-associated X protein (Bax), cytochrome c, caspase-3 expressions and Bax/Bcl-2 ratio in the periinfarct cortex after cerebral I/R injury. Conclusion: Our findings suggest that EE treatment inhibits neuronal apoptosis in the periinfarct cortex after focal cerebral I/R injury, which may be one of the possible mechanisms underlying the neuroprotective effects of EE.
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40
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Kalra J, Dhar A. Double-stranded RNA-dependent protein kinase signalling and paradigms of cardiometabolic syndrome. Fundam Clin Pharmacol 2017; 31:265-279. [PMID: 27992964 DOI: 10.1111/fcp.12261] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Revised: 11/30/2016] [Accepted: 12/16/2016] [Indexed: 12/28/2022]
Affiliation(s)
- Jaspreet Kalra
- Department of Pharmacy; Birla Institute of Technology and Sciences Pilani, Hyderabad Campus; Jawahar Nagar Shameerpet, Hyderabad Andhra Pradesh 500078 India
| | - Arti Dhar
- Department of Pharmacy; Birla Institute of Technology and Sciences Pilani, Hyderabad Campus; Jawahar Nagar Shameerpet, Hyderabad Andhra Pradesh 500078 India
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41
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Affiliation(s)
- Anthony Letai
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215
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42
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Anti-tumor effect of evodiamine by inducing Akt-mediated apoptosis in hepatocellular carcinoma. Biochem Biophys Res Commun 2017; 485:54-61. [PMID: 28189683 DOI: 10.1016/j.bbrc.2017.02.017] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Accepted: 02/05/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Evodiamine is an alkaloid extracted from Euodia rutaecarpa (Juss.) Benth. There is little information about the mechanisms of evodiamine on the apoptosis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS A xenograft model and CCK8 assay were used to investigate the anti-HCC effect of evodiamine. The effect of evodiamine on apoptosis was evaluated by DAPI staining and flow cytometry. Western blot analyses and immunohistochemistry were processed to assess the protein expressions of Akt and apoptotic proteins. RESULTS Evodiamine suppressed tumor growth, improved the expression of cleaved-caspase3 and decreased tumor specific growth factor (TSGF) and alpha fetoprotein (AFP) activities. Furthermore, evodiamine inhibited cell viability and induced cell cycle arrest. DAPI staining revealed nuclear condensation in evodiamine-treated groups. Meanwhile, evodiamine increased the number of apoptotic cells. Furthermore, evodiamine suppressed Akt and regulated apoptotic proteins in HepG2 cells. Evodiamine decreased p-Akt levels activated by SC79, which led to the increase of bax/bcl-2 and cleaved-caspase3. CONCLUSIONS Our findings suggested that evodiamine could exert anti-HCC effect through inducing Akt-mediated apoptosis. Evodiamine has the potential to be a therapeutic medicine for HCCs.
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Abstract
Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state.
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Affiliation(s)
- Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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44
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Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W, McBrayer SK, Cantlon A, Fisch S, Golomb-Mello G, Ryan JA, Deng J, Jian B, Corbett C, Goldenberg M, Madsen JR, Liao R, Walsh D, Sedivy J, Murphy DJ, Carrasco DR, Robinson S, Moslehi J, Letai A. Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell 2017; 31:142-156. [PMID: 28017613 PMCID: PMC5363285 DOI: 10.1016/j.ccell.2016.11.011] [Citation(s) in RCA: 177] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 09/13/2016] [Accepted: 11/17/2016] [Indexed: 01/20/2023]
Abstract
It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.
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Affiliation(s)
- Kristopher A Sarosiek
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Cameron Fraser
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA
| | | | - Patrick D Bhola
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Weiting Chang
- Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Samuel K McBrayer
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Adam Cantlon
- Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Sudeshna Fisch
- Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Gail Golomb-Mello
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
| | - Jeremy A Ryan
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Jing Deng
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Brian Jian
- Department of Neurosurgery, Kaiser Permanente, Sacramento, CA 95815, USA
| | - Chris Corbett
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA
| | - Marti Goldenberg
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA
| | - Joseph R Madsen
- Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA
| | - Ronglih Liao
- Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Dominic Walsh
- Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - John Sedivy
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
| | - Daniel J Murphy
- Cancer Research UK Beatson Institute, Glasgow G61 1BD, Scotland; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, Scotland
| | - Daniel Ruben Carrasco
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Shenandoah Robinson
- Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02115, USA
| | - Javid Moslehi
- Division of Cardiovascular Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Division of Hematology-Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Cardio-Oncology Program, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Anthony Letai
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
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Baraka A, Shorbagy SE, Elfarargy OM, Haggag R, Abdelaziz LA, Elsayed SF, Elbana KA. Prognostic Significance of Apoptosis Regulators in B-Cell Chronic Lymphocytic Leukemia. ACTA ACUST UNITED AC 2017. [DOI: 10.4236/jct.2017.84032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Sutherland C, Cui Y, Mao H, Hurley LH. A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III1. J Am Chem Soc 2016; 138:14138-14151. [DOI: 10.1021/jacs.6b09196] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Caleb Sutherland
- University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, Arizona 85724, United States
| | - Yunxi Cui
- Department
of Chemistry and Biochemistry and School of Biomedical Sciences, Kent State University, Kent, Ohio 44242, United States
| | - Hanbin Mao
- Department
of Chemistry and Biochemistry and School of Biomedical Sciences, Kent State University, Kent, Ohio 44242, United States
| | - Laurence H. Hurley
- University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, Arizona 85724, United States
- University of Arizona, College of Pharmacy, 1703 East Mabel Street, Tucson, Arizona 85721, United States
- BIO5 Institute, 1657 East
Helen Street, Tucson, Arizona 85721, United States
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47
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Abstract
Apoptosis is a form of cellular suicide in which the cell activates an intrinsic program to bring about its own demise. Recognized for years as the mechanism by which developing cells are lost naturally, it has become apparent recently that this same process may play an important role in many acute and chronic diseases in which neural cell death occurs, such as stroke and Alzheimer's disease. This growing recognition suggests that a knowledge of the gene products controlling this process may lead to improved treatments for some disease states, as well as to improved understanding of neuronal development, physiology, and pathophysiology. Some controls with important roles in neural apoptosis have been identified, and these controls, as well as their putative mechanisms of action, are described in this article. NEUROSCIENTIST 2:181-190, 1996
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Affiliation(s)
- Dale E. Bredesen
- Program on Aging La Jolla Cancer Research Foundation
La Jolla, California
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Ozdek A, Sarac S, Akyol MU, Sungur A, Yilmaz T. C-Myc And Bcl-2 Expression In Supraglottic Squamous Cell Carcinoma of the Larynx. Otolaryngol Head Neck Surg 2016; 131:77-83. [PMID: 15243561 DOI: 10.1016/j.otohns.2004.02.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
OBJECTIVES: To evaluate the expression and prognostic significance of c-myc and bcl-2 oncogenes in squamous cell carcinoma (SCC) of the supraglottic larynx. STUDY DESIGN: A retrospective cohort study of 61 patients who underwent surgery for SCC of the supraglottic larynx. Gender, age, TNM status, operative procedure, recurrences, and disease-free survival periods were recorded. METHODS: Hematoxylin and eosin-stained sections were reexamined for grade, invasion of tumor margins, lymphovascular invasion, lymphocyte infiltration, and perineural invasion. Immunohistochemical detection of c-myc and bcl-2 oncogenes was performed using monoclonal antibodies. RESULTS: No correlation was observed between either c-myc or bcl-2 and the clinical and histopathologic parameters. Survival analysis revealed no correlation of either c-myc ( P = 0.88) or bcl-2 ( P = 0.85) with the disease-free survival. c-myc expression was found to be significantly higher in bcl-2-positive patients ( P = 0.001). CONCLUSION: Neither c-myc nor bcl-2 had shown to be prognostic factor for laryngeal carcinoma in this present study. Correlation between c-myc and bcl-2 supports the experimental observations of cooperative action between these two genes in tumorigenesis.
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Affiliation(s)
- Ali Ozdek
- Ankara Training and Research Hospital, Ankara, Turkey.
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Green DR. The cell's dilemma, or the story of cell death: an entertainment in three acts. FEBS J 2016; 283:2568-76. [PMID: 26787595 DOI: 10.1111/febs.13658] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 01/13/2016] [Indexed: 12/28/2022]
Abstract
Cells. They assemble, thrive, and cooperate to compose an organism, simple or complex. And like any living thing, they die. They die by catastrophe, they become sabotaged by condition, or they remove themselves on command from within or without. Each small life is followed by a death, to the benefit or the harm of the whole. Our story, here, is not of how each quietus occurs, but instead, of our ongoing effort to understand these tiny demises, to manipulate them, and to some day control them.
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Delbridge ARD, Grabow S, Strasser A, Vaux DL. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 2016; 16:99-109. [PMID: 26822577 DOI: 10.1038/nrc.2015.17] [Citation(s) in RCA: 570] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The 'hallmarks of cancer' are generally accepted as a set of genetic and epigenetic alterations that a normal cell must accrue to transform into a fully malignant cancer. It follows that therapies designed to counter these alterations might be effective as anti-cancer strategies. Over the past 30 years, research on the BCL-2-regulated apoptotic pathway has led to the development of small-molecule compounds, known as 'BH3-mimetics', that bind to pro-survival BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and, specifically, its roles in cancer development and therapy.
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Affiliation(s)
- Alex R D Delbridge
- Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia
| | - Stephanie Grabow
- Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia
| | - Andreas Strasser
- Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia
| | - David L Vaux
- Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology, University of Melbourne, Victoria, Australia
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