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Ma B, Sang Y, Du X, Zhang Y, Yin M, Xu W, Liu W, Lu J, Guan Q, Wang Y, Liao T, Wang Y, Xiang J, Shi R, Qu N, Ji Q, Zhang J, Ji D, Wang Y. Targeting CDK2 Confers Vulnerability to Lenvatinib Via Driving Senescence in Anaplastic Thyroid Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413514. [PMID: 39716890 PMCID: PMC11831524 DOI: 10.1002/advs.202413514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/24/2024] [Indexed: 12/25/2024]
Abstract
Anaplastic thyroid cancer (ATC) is the most lethal tumor arising from thyroid follicular epithelium. Lenvatinib is an off-label use option for ATC patients in many countries but an approved prescription in Japan. However, lenvatinib resistance is a substantial clinical challenge. Clinical ATC samples including lenvatinib-resistant tumors are used to build patient-derived cells and patient-derived xenografts. High-throughput drug screening and synergy analyses are performed to identify an effective combination partner for lenvatinib. Cellular functions are detected by cell senescence, apoptosis, cell cycle, cell viability and colony formation assays. CDK2 inhibition showed the significant synthetic lethality with lenvatinib via inhibiting G1/S transition and inducing cell senescence in ATC. High expression of CDK2 is associated with lenvatinib resistance and poor clinical outcomes of ATC patients. Lenvatinib increased protein expression of CDK2 in lenvatinib-resistant ATC cells. Mechanistically, lenvatinib inhibited protein degradation of CDK2 via reducing CDK2's interaction with the RACK1-FBW7 complex, which is involved in ubiquitination and subsequent proteasomal degradation of CDK2. Combination of CDK2 inhibitors in clinical trials (Dinaciclib or PF-07104091) and lenvatinib markedly suppressed growth of xenograft tumors from the lenvatinib-resistant patient. The findings support the combination therapy strategy of lenvatinib and CDK2 inhibitor for lenvatinib-resistant ATC patients with high CDK2 expression.
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Affiliation(s)
- Ben Ma
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Youzhou Sang
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
| | - Xiaoxue Du
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Yanzhi Zhang
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Min Yin
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Weibo Xu
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Wanlin Liu
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Jiayi Lu
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Qing Guan
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Yunjun Wang
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Tian Liao
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Yuting Wang
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Jun Xiang
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Rongliang Shi
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Ning Qu
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Qinghai Ji
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Jiwei Zhang
- The MOE Key Laboratory for Standardization of Chinese MedicinesInstitute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghai201203P. R. China
| | - Dongmei Ji
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
| | - Yu Wang
- Department of Head and Neck SurgeryFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
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Zheng Q, Peng Q, Shen J, Liu H. Efficient analysis of toxicity and mechanisms of Acetyl tributyl citrate on aging with network toxicology and molecular docking strategy. Toxicology 2025; 510:154009. [PMID: 39580138 DOI: 10.1016/j.tox.2024.154009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 11/25/2024]
Abstract
The aim of this study was to apply a network toxicology strategy to investigate the potential toxicity and the molecular mechanisms underlying the aging-induced toxicity of acetyl tributyl citrate (ATBC). Utilizing the ChEMBL, SwissTargetPrediction, and CellAge databases, we identified 32 potential targets associated with ATBC exposure and aging. Subsequent optimization by STRING and Cytoscape software highlighted 11 core targets, including EGFR, STAT3, and BCL-2. A comprehensive analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that core targets of ATBC-induced senescence were predominantly enriched in pathways related to the positive regulation of cell proliferation, telomere shortening, cancer, and cellular senescence. Among these pathways, we selected four core genes of the cellular senescence pathway (MAPK14, CDK2, MDM2, and PIK3CA) for molecular docking with Autodock, which confirmed the high binding affinity between ATBC and the core targets. In conclusion, these findings indicate that ATBC may contribute to human aging by modulating the positive regulation of cell proliferation, the telomere shortening pathway, the cancer-related pathway, and the cellular senescence pathway. This study establishes a theoretical basis for exploring the molecular mechanisms of human aging induced by ATBC, alongside a systematic and effective framework for researchers to assess the potential toxicity of various chemical products.
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Affiliation(s)
- Qiu Zheng
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Qingping Peng
- Collage of Integrated Traditional Chines and Western Medicine, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Jianlin Shen
- Department of Orthopedics, Affiliated Hospital of Putian University, Putian, 351100,China; Central Laboratory,Affiliated Hospital of Putian University, Putian 351100, China.
| | - Huan Liu
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China.
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Kim JW, Bae SH, Moon Y, Kim EK, Kim Y, Park YG, Han MR, Sohn J. Transcriptomic analysis of cellular senescence induced by ectopic expression of ATF6α in human breast cancer cells. PLoS One 2024; 19:e0309749. [PMID: 39466820 PMCID: PMC11515977 DOI: 10.1371/journal.pone.0309749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/17/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND The transcriptomic profile of cellular senescence is strongly associated with distinct cell types, the specific stressors triggering senescence, and temporal progression through senescence stages. This implies the potential necessity of conducting separate investigations for each cell type and a stressor inducing senescence. To elucidate the molecular mechanism that drives endoplasmic reticulum (ER) stress-induced cellular senescence in MCF-7 breast cancer cells, with a particular emphasis on the ATF6α branch of the unfolded protein response. We conducted transcriptomic analysis on MCF-7 cells by ectopic expression of ATF6α. METHODS Transcriptomic sequencing was conducted on MCF-7 cells at 6 and 9 hours post senescence induction through ATF6α ectopic expression. Comprehensive analyses encompassing enriched functional annotation, canonical pathway analysis, gene network analysis, upstream regulator analysis and gene set enrichment analysis were performed on Differentially Expressed Genes (DEGs) at 6 and 9 hours as well as time-related DEGs. Regulators and their targets identified from the upstream regulator analysis were validated through RNA interference, and their impact on cellular senescence was assessed by senescence-associated β-galactosidase staining. RESULTS ATF6α ectopic expression resulted in the identification of 12 and 79 DEGs at 6 and 9 hours, respectively, employing criteria of a false discovery rate < 0.05 and a lower fold change (FC) cutoff |log2FC| > 1. Various analyses highlighted the involvement of the UPR and/or ER Stress Pathway. Upstream regulator analysis of 9 hour-DEGs identified six regulators and eleven target genes associated with processes related to cytostasis and 'cell viability and cell death of connective tissue cells.' Validation confirmed the significance of MAP2K1/2, GPAT4, and PDGF-BB among the regulators and DDIT3, PPP1R15A, and IL6 among the targets. CONCLUSION Transcriptomic analyses and validation reveal the importance of the MAP2K1/2/GPAT4-DDIT3 pathway in driving cellular senescence following ATF6α ectopic expression in MCF-7 cells. This study contributes to our understanding of the initial molecular events underlying ER stress-induced cellular senescence in breast cancer cells, providing a foundation for exploring cell type- and stressor-specific responses in cellular senescence induction.
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Affiliation(s)
- Ju Won Kim
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea
| | - So-Hyun Bae
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, South Korea
| | - Yesol Moon
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea
- Korea Institute of Molecular Medicine and Nutrition, Seoul, South Korea
| | - Eun Kyung Kim
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea
- Korea Institute of Molecular Medicine and Nutrition, Seoul, South Korea
| | - Yongjin Kim
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea
- Korea Institute of Molecular Medicine and Nutrition, Seoul, South Korea
| | - Yun Gyu Park
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea
- Korea Institute of Molecular Medicine and Nutrition, Seoul, South Korea
| | - Mi-Ryung Han
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, South Korea
| | - Jeongwon Sohn
- Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea
- Korea Institute of Molecular Medicine and Nutrition, Seoul, South Korea
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Liang K, Wang Q, Qiu L, Gong X, Chen Z, Zhang H, Ding K, Liu Y, Wei J, Lin S, Fu S, Du H. Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer. Int J Mol Sci 2023; 24:15658. [PMID: 37958642 PMCID: PMC10650476 DOI: 10.3390/ijms242115658] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Various studies have shown that the cell-cycle-related regulatory proteins UBE2C, PLK1, and BIRC5 promote cell proliferation and migration in different types of cancer. However, there is a lack of in-depth and systematic research on the mechanism of these three as therapeutic targets. In this study, we found a positive correlation between the expression of UBE2C and PLK1/BIRC5 in the Cancer Genome Atlas (TCGA) database, revealing a potential combination therapy candidate for pan-cancer. Quantitative real-time PCR (qRT-PCR), Western blotting (WB), cell phenotype detection, and RNA-seq techniques were used to evidence the effectiveness of the combination candidate. We found that combined interference of UBE2C with PLK1 and UBE2C with BIRC5 affected metabolic pathways by significantly downregulating the mRNA expression of IDH1 and ACLY, which was related to the synthesis of acetyl-CoA. By combining the PLK1 inhibitor volasertib and the ACLY inhibitor bempedoic acid, it showed a higher synergistic inhibition of cell viability and higher synergy scores in seven cell lines, compared with those of other combination treatments. Our study reveals the potential mechanisms through which cell-cycle-related genes regulate metabolism and proposes a potential combined targeted therapy for patients with higher PLK1 and ACLY expression in pan-cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Hongli Du
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China; (K.L.); (Q.W.); (L.Q.); (X.G.); (Z.C.); (H.Z.); (K.D.); (Y.L.); (J.W.); (S.L.); (S.F.)
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Cao B, Zhang K, Pan C, Dong Y, Lu F. NEK8 regulates colorectal cancer progression via phosphorylating MYC. Cell Commun Signal 2023; 21:209. [PMID: 37596667 PMCID: PMC10436496 DOI: 10.1186/s12964-023-01215-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 07/04/2023] [Indexed: 08/20/2023] Open
Abstract
Radiotherapy and chemotherapy remain the mainstay of treatment for colorectal cancer (CRC), although their efficacy is limited. A detailed understanding of the molecular mechanisms underlying CRC progression could lead to the development of new therapeutic strategies. Although it has been established that MYC signaling is dysregulated in various human cancers, direct targeting MYC remains challenging due to its "undruggable" protein structure. Post-translational modification of proteins can affect their stability, activation, and subcellular localization. Hence, targeting the post-translational modification of MYC represents a promising approach to disrupting MYC signaling. Herein, we revealed that NEK8 positively regulates CRC progression by phosphorylating c-MYC protein at serine 405, which exhibited enhanced stability via polyubiquitination. Our findings shed light on the role of NEK8/MYC signaling in CRC progression, offering a novel and helpful target for colorectal cancer treatment. Video Abstract.
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Affiliation(s)
- Beibei Cao
- Department of Breast Surgery, Henan Provincial People's Hospital, Zhengzhou City, China
| | - Kailun Zhang
- Zhengzhou University People's Hospital, Zhengzhou City, China
| | - Changjie Pan
- Zhengzhou University People's Hospital, Zhengzhou City, China
| | - Yifei Dong
- Zhengzhou University People's Hospital, Zhengzhou City, China
| | - Feng Lu
- Department of Breast Surgery, Henan Provincial People's Hospital, Zhengzhou City, China.
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Fan W, Li X. The SIRT1-c-Myc axis in regulation of stem cells. Front Cell Dev Biol 2023; 11:1236968. [PMID: 37554307 PMCID: PMC10405831 DOI: 10.3389/fcell.2023.1236968] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/10/2023] [Indexed: 08/10/2023] Open
Abstract
SIRT1 is the most conserved mammalian NAD+-dependent protein deacetylase. Through deacetylation of transcriptional factors and co-factors, this protein modification enzyme is critically involved in metabolic and epigenetic regulation of stem cells, which is functionally important in maintaining their pluripotency and regulating their differentiation. C-Myc, a key member of Myc proton-oncogene family, is a pivotal factor for transcriptional regulation of genes that control acquisition and maintenance of stemness. Previous cancer research has revealed an intriguing positive feedback loop between SIRT1 and c-Myc that is crucial in tumorigenesis. Recent literature has uncovered important functions of this axis in regulation of maintenance and differentiation of stem cells, including pluripotent stem cells and cancer stem cells. This review highlights recent advances of the SIRT1-c-Myc axis in stem cells.
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Affiliation(s)
- Wei Fan
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, United States
| | - Xiaoling Li
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, United States
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Zhou Y, Nishiura A, Morikuni H, Deng W, Tsujibayashi T, Momota Y, Azetsu Y, Takami M, Honda Y, Matsumoto N. RANKL + senescent cells under mechanical stress: a therapeutic target for orthodontic root resorption using senolytics. Int J Oral Sci 2023; 15:20. [PMID: 37253719 DOI: 10.1038/s41368-023-00228-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 04/29/2023] [Accepted: 05/04/2023] [Indexed: 06/01/2023] Open
Abstract
In dentistry, orthodontic root resorption is a long-lasting issue with no effective treatment strategy, and its mechanisms, especially those related to senescent cells, remain largely unknown. Here, we used an orthodontic intrusion tooth movement model with an L-loop in rats to demonstrate that mechanical stress-induced senescent cells aggravate apical root resorption, which was prevented by administering senolytics (a dasatinib and quercetin cocktail). Our results indicated that cementoblasts and periodontal ligament cells underwent cellular senescence (p21+ or p16+) and strongly expressed receptor activator of nuclear factor-kappa B (RANKL) from day three, subsequently inducing tartrate-resistant acid phosphatase (TRAP)-positive odontoclasts and provoking apical root resorption. More p21+ senescent cells expressed RANKL than p16+ senescent cells. We observed only minor changes in the number of RANKL+ non-senescent cells, whereas RANKL+ senescent cells markedly increased from day seven. Intriguingly, we also found cathepsin K+p21+p16+ cells in the root resorption fossa, suggesting senescent odontoclasts. Oral administration of dasatinib and quercetin markedly reduced these senescent cells and TRAP+ cells, eventually alleviating root resorption. Altogether, these results unveil those aberrant stimuli in orthodontic intrusive tooth movement induced RANKL+ early senescent cells, which have a pivotal role in odontoclastogenesis and subsequent root resorption. These findings offer a new therapeutic target to prevent root resorption during orthodontic tooth movement.
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Affiliation(s)
- Yue Zhou
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan
| | - Aki Nishiura
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan.
| | - Hidetoshi Morikuni
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan
| | - Wenqi Deng
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan
| | - Toru Tsujibayashi
- Department of Physics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan
| | - Yoshihiro Momota
- Department of Anesthesiology, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan
| | - Yuki Azetsu
- Department of Pharmacology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawaku, Tokyo, Japan
| | - Masamichi Takami
- Department of Pharmacology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawaku, Tokyo, Japan
| | - Yoshitomo Honda
- Department of Oral Anatomy, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan.
| | - Naoyuki Matsumoto
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka, Japan
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The "Superoncogene" Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme. Int J Mol Sci 2023; 24:ijms24044217. [PMID: 36835628 PMCID: PMC9966483 DOI: 10.3390/ijms24044217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.
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Multi-Omics Analysis Reveals the Potential Effects of Maternal Dietary Restriction on Fetal Muscle Growth and Development. Nutrients 2023; 15:nu15041051. [PMID: 36839409 PMCID: PMC9964303 DOI: 10.3390/nu15041051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/15/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
In terms of fetal muscle growth, development, and health, maternal nutrition is a crucial influence, although the exact biochemical mechanism by which this occurs is still not fully understood. To examine the potential impacts of maternal dietary restriction on fetal muscle development, the sheep maternal dietary restriction model was developed for this study. In our study, 12 pregnant ewes were evenly split into two experimental groups and fed either 75% or 100% of a maternal nutrient. In addition, a multi-omics analysis was used to study the embryonic longissimus dorsis on gestational days (GD) 85 and 135. The fetal weight at GD 135 was significantly below normal due to the maternal restricted diet (p < 0.01). When fetuses were exposed to the dietary deficit, 416 mRNAs and 40 proteins were significantly changed. At GD 85, the multi-omics analysis revealed that maternal dietary restriction led to a significant up-regulation of the cell cycle regulator CDK2 gene in the cellular senescence signaling pathway, and the results of the qRT-PCR were similar to the multi-omics analysis, which showed that SIX1, PAX7, the cell cycle factors CDK4 and CDK6, and the BCL-2 apoptosis factor were up-regulated and several skeletal muscle marker genes, such as MYF5 and MyoD were down-regulated. At GD 135, maternal dietary restriction blocks the muscle fiber differentiation and maturation. The multi-omics analysis revealed that the TEAD1 gene was in the Hippo signaling pathway, the muscle marker genes MYF5 and MyoG were significantly down-regulated, and the TEAD1 binding of the down-regulated VGLL3 gene might be potential mechanisms affecting myofiber differentiation and maturation. Knocking down the CDK2 gene could inhibit the proliferation of primary embryonic myoblasts, and the expression levels of cell cycle regulatory factors CDK4 and CDK6 were significantly changed. Under low nutrient culture conditions, the number of myoblasts decreased and the expression of CDK2, CDK6, MYF5, PAX7 and BCL-2 changed, which was in perfect agreement with the multi-omics analysis. All of the findings from our study helped to clarify the potential effects of maternal dietary restriction on fetal muscle growth and development. They also provided a molecular foundation for understanding the molecular regulatory mechanisms of maternal nutrition on fetal muscle growth and development, as well as for the development of new medications and the management of related metabolic diseases.
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Zarneshan SN, Fakhri S, Bachtel G, Bishayee A. Exploiting pivotal mechanisms behind the senescence-like cell cycle arrest in cancer. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 135:1-19. [PMID: 37061329 DOI: 10.1016/bs.apcsb.2022.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Senescence-like cell cycle arrest is a critical state of cancer initiation and progression. Senescence is an irreversible cell cycle arrest in response to stress induced by extrinsic and intrinsic stimuli, including oxidative/genotoxic stress, oncogenic activation, irradiation, mitochondrial malfunction, or chemotherapeutic drugs. Several signaling pathways are involved in senescence-like cell cycle arrest, which is primarily induced by the activation of p53/p21-dependent apoptotic pathways and suppressing p16INK4A/retinoblastoma protein (pRB)-dependent oncogenic pathways. p21 is necessary for proper cell cycle advancement, is involved in cell death, and mediates p53-dependent cell cycle arrest caused by DNA damage. pRB's role in tumor suppression is through modulation of the G1 checkpoint in the cell cycle, as it has the ability to block S-phase entry and cell growth. The aforementioned pathways are also highly interconnected with significant crosstalk, such as cyclin-dependent kinases (CDK)/cyclin complexes, and the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex. The primary regulators of transcription are p53 and pRB, which maintain the senescent state through negative control of the cell cycle and process of tumorigenesis. Because CDK inhibitors comprise negative regulators of cell cycle progress, they are fundamental parts of each route. Prolonged overexpression of any of these four fundamental elements (p16, p53, p21, and pRB) suffices to induce senescence, demonstrating how the regulatory DREAM complex causes senescence and how its malfunction results in cell cycle progression. The present chapter aims at revealing the pivotal mechanisms behind the senescence-like cell cycle arrest in cancer.
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11
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Shang D, Li Z, Tan X, Liu H, Tu Z. Inhibitory effects and molecular mechanisms of ginsenoside Rg1 on the senescence of hematopoietic stem cells. Fundam Clin Pharmacol 2022; 37:509-517. [PMID: 36582074 DOI: 10.1111/fcp.12863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/09/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022]
Abstract
Hematopoietic stem cells (HSCs) produce all blood cell lineages and maintain life-long hematopoiesis. However, the self-renewal ability and differentiation capacity of HSCs reduces with age. The senescence of HSCs can lead to the imbalance of hematopoietic homeostasis and immune disorder and induce a variety of age-related diseases. Recent studies have shown that therapeutic interventions targeting the senescence of HSCs may prevent disease progression. Ginsenoside Rg1 (Rg1), extracted from roots or stems of ginseng, has beneficial antiaging activities. It has been reported that Rg1 can inhibit the senescence of HSCs. Here, we reviewed recent advances of Rg1 in inhibiting the senescence of HSCs and discussed related molecular mechanisms. Bioinformatics and network databases have been widely applied to drug discoveries. Here, we predicted potential antiaging targets of Rg1 explored by bioinformatic methods, which may help discover new targets of Rg1 and provide novel strategies for delaying the aging process of HSCs.
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Affiliation(s)
- Dongsheng Shang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhihuan Li
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiaoli Tan
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhigang Tu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
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12
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Kang D, Baek Y, Lee JS. Mechanisms of RNA and Protein Quality Control and Their Roles in Cellular Senescence and Age-Related Diseases. Cells 2022; 11:cells11244062. [PMID: 36552825 PMCID: PMC9777292 DOI: 10.3390/cells11244062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/04/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Cellular senescence, a hallmark of aging, is defined as irreversible cell cycle arrest in response to various stimuli. It plays both beneficial and detrimental roles in cellular homeostasis and diseases. Quality control (QC) is important for the proper maintenance of cellular homeostasis. The QC machineries regulate the integrity of RNA and protein by repairing or degrading them, and are dysregulated during cellular senescence. QC dysfunction also contributes to multiple age-related diseases, including cancers and neurodegenerative, muscle, and cardiovascular diseases. In this review, we describe the characters of cellular senescence, discuss the major mechanisms of RNA and protein QC in cellular senescence and aging, and comprehensively describe the involvement of these QC machineries in age-related diseases. There are many open questions regarding RNA and protein QC in cellular senescence and aging. We believe that a better understanding of these topics could propel the development of new strategies for addressing age-related diseases.
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Affiliation(s)
- Donghee Kang
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon 22212, Republic of Korea
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea
| | - Yurim Baek
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon 22212, Republic of Korea
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Republic of Korea
| | - Jae-Seon Lee
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon 22212, Republic of Korea
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Republic of Korea
- Correspondence: ; Tel.: +82-32-860-9832; Fax: +82-32-885-8302
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13
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Sun J, Wang X, Shen Q, Wang M, Chen S, Zhang X, Huang Y, Zhang Z, Li W, Yuan Y, Huang Z. DNASE1L3 inhibits hepatocellular carcinoma by delaying cell cycle progression through CDK2. Cell Oncol 2022; 45:1187-1202. [PMID: 36327092 DOI: 10.1007/s13402-022-00709-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2022] [Indexed: 11/06/2022] Open
Abstract
PURPOSE Dysregulated cell cycle targeting is a well-established therapeutic strategy against hepatocellular carcinoma (HCC). Dissecting the underlying mechanism may improve the efficacy of HCC therapy. METHODS HCC data from TCGA and new clinical samples were used for DNASE1L3 expression analysis and for assessing its correlation with HCC development. The in vitro function of DNASE1L3 in HCC cell proliferation, colony formation, migration and invasion was assessed using RTCA, CCK-8 and transwell assays and the in vivo function in subcutaneous tumor formation in a xenograft nude mouse model. The role of DNASE1L3 in HCC tumorigenesis was further verified in AKT/NRASV12-induced and DEN/CCl4-induced primary liver cancers in wildtype and Dnase1l3-/- mice. Finally, RNA-Seq analysis followed by biochemical methods including cell cycle, immunofluorescence, co-immunoprecipitation and Western blotting assays were employed to reveal the underlying mechanism. RESULTS We found that DNASE1L3 was significantly downregulated and served as a favorable prognostic factor in HCC. DNASE1L3 dramatically attenuated HCC cell proliferation, colony formation, migration and invasion in vitro and reduced subcutaneous tumor formation in nude mice in vivo. Furthermore, DNASE1L3 overexpression dampened AKT/NRASV12-induced mouse liver cancer in wildtype mice and DNASE1L3 deficiency worsened DEN/CCl4-induced liver cancer in Dnase1l3-/- mice. Systemic analysis revealed that DNASE1L3 impaired HCC cell cycle progression by interacting with CDK2 and inhibiting CDK2-stimulated E2F1 activity. C-terminal deletion (DNASE1L3ΔCT) diminished the interaction with CDK2 and abrogated the inhibitory function against HCC. CONCLUSION Our study unveils DNASE1L3 as a novel HCC cell cycle regulator and tumor suppressor. DNASE1L3 impairs HCC tumorigenesis by delaying cell cycle progression possibly through disrupting the positive E2F1-CDK2 regulatory loop. DNASE1L3 may serve as a target for the development of novel therapeutic strategies against HCC.
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Affiliation(s)
- Jiaqi Sun
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Xiyang Wang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Qingsong Shen
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Min Wang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Shuxian Chen
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Xuechun Zhang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Yongping Huang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Zhonglin Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wenhua Li
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zan Huang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China.
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14
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Luo Y, Liu H, Fu H, Ding GS, Teng F. A cellular senescence-related classifier based on a tumorigenesis- and immune infiltration-guided strategy can predict prognosis, immunotherapy response, and candidate drugs in hepatocellular carcinoma. Front Immunol 2022; 13:974377. [PMID: 36458010 PMCID: PMC9705748 DOI: 10.3389/fimmu.2022.974377] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/25/2022] [Indexed: 09/05/2023] Open
Abstract
BACKGROUND Cellular senescence plays an irreplaceable role in tumorigenesis, progression, and tumor microenvironment (TME) remodeling. However, to date, there is limited research delineating the landscape of cellular senescence in hepatocellular carcinoma (HCC), and an improved understanding on the interaction of tumor-associated cellular senescence with HCC prognosis, TME, and response to immunotherapy is warrant. METHODS Tumorigenic and immune infiltration-associated senescence genes were determined by weighted gene co-expression network analysis (WGCNA) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm, and subsequently, a prognostic scoring model (named TIS) was constructed using multiple survival analysis algorithms to classify the senescence-related subtypes of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were conducted to identify the distinct hallmark pathways between high- and low-risk subtypes. Additionally, we carried out correlation analyses for TIS and clinical traits, senescence-associated secretory phenotype (SASP), immune infiltration and evasion, immune checkpoint factors, drug response, and immunotherapeutic efficacy. External experimental validation was conducted to delineate the association of CPEP3 (a TIS gene) with HCC phenotypes through assays of proliferation, colony formation, and invasion. RESULTS A five-gene TIS, composed of NET1, ATP6V0B, MMP1, GTDC1, and CPEB3, was constructed and validated using TCGA and ICGC datasets, respectively, and showed a highly robust and plausible signature for overall survival (OS) prediction of HCC in both training and validation cohorts. Patients in the TIS-high group were accompanied by worse OS, activation of carcinogenetic pathways, infiltration of immunosuppressive cells, exclusion of effector killing cells, overexpression of immunomodulatory genes and SASP, and unsatisfied response to immunotherapy. In response to anticancer drugs, patients in the TIS-high group exhibited enhanced susceptibility to several conventional chemotherapeutic agents (5-fluorouracil, docetaxel, doxorubicin, gemcitabine, and etoposide), as well as several inhibitors of pathways involved in cellular senescence (cell-cycle inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, PI3K-AKT pathway inhibitors, and multikinase inhibitors). Additionally, four putative drugs (palbociclib, JAK3 inhibitor VI, floxuridine, and lestaurtinib) were identified as potential compounds for patients in the TIS-high group. Notably, in vitro functional validation showed that CPEB3 knockdown boosted the phenotypes of proliferation, clonogenicity, and invasion in HCC cells, whereas CPEB3 overexpression attenuated these phenotypes. CONCLUSIONS Our study provides comprehensive clues demonstrating the role of novel TIS in predicting HCC prognosis, immunotherapeutic response, and candidate drugs. This work highlights the significance of tumorigenesis- and immune infiltration-related cellular senescence in cancer therapy.
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Affiliation(s)
- Yi Luo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Hao Liu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Guo-Shan Ding
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai, China
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15
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Donati G, Amati B. MYC and therapy resistance in cancer: risks and opportunities. Mol Oncol 2022; 16:3828-3854. [PMID: 36214609 PMCID: PMC9627787 DOI: 10.1002/1878-0261.13319] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/08/2022] [Accepted: 10/06/2022] [Indexed: 12/24/2022] Open
Abstract
The MYC transcription factor, encoded by the c-MYC proto-oncogene, is activated by growth-promoting signals, and is a key regulator of biosynthetic and metabolic pathways driving cell growth and proliferation. These same processes are deregulated in MYC-driven tumors, where they become critical for cancer cell proliferation and survival. As other oncogenic insults, overexpressed MYC induces a series of cellular stresses (metabolic, oxidative, replicative, etc.) collectively known as oncogenic stress, which impact not only on tumor progression, but also on the response to therapy, with profound, multifaceted consequences on clinical outcome. On one hand, recent evidence uncovered a widespread role for MYC in therapy resistance in multiple cancer types, with either standard chemotherapeutic or targeted regimens. Reciprocally, oncogenic MYC imparts a series of molecular and metabolic dependencies to cells, thus giving rise to cancer-specific vulnerabilities that may be exploited to obtain synthetic-lethal interactions with novel anticancer drugs. Here we will review the current knowledge on the links between MYC and therapeutic responses, and will discuss possible strategies to overcome resistance through new, targeted interventions.
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Affiliation(s)
- Giulio Donati
- European Institute of Oncology (IEO) – IRCCSMilanItaly
| | - Bruno Amati
- European Institute of Oncology (IEO) – IRCCSMilanItaly
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16
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Piskorz WM, Cechowska-Pasko M. Senescence of Tumor Cells in Anticancer Therapy—Beneficial and Detrimental Effects. Int J Mol Sci 2022; 23:ijms231911082. [PMID: 36232388 PMCID: PMC9570404 DOI: 10.3390/ijms231911082] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/16/2022] [Accepted: 09/18/2022] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence process results in stable cell cycle arrest, which prevents cell proliferation. It can be induced by a variety of stimuli including metabolic stress, DNA damage, telomeres shortening, and oncogenes activation. Senescence is generally considered as a process of tumor suppression, both by preventing cancer cells proliferation and inhibiting cancer progression. It can also be a key effector mechanism for many types of anticancer therapies such as chemotherapy and radiotherapy, both directly and through bioactive molecules released by senescent cells that can stimulate an immune response. Senescence is characterized by a senescence-associated secretory phenotype (SASP) that can have both beneficial and detrimental impact on cancer progression. Despite the negatives, attempts are still being made to use senescence to fight cancer, especially when it comes to senolytics. There is a possibility that a combination of prosenescence therapy—which targets tumor cells and causes their senescence—with senotherapy—which targets senescent cells, can be promising in cancer treatment. This review provides information on cellular senescence, its connection with carcinogenesis and therapeutic possibilities linked to this process.
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FBXW7 inactivation induces cellular senescence via accumulation of p53. Cell Death Dis 2022; 13:788. [PMID: 36104351 PMCID: PMC9475035 DOI: 10.1038/s41419-022-05229-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 01/21/2023]
Abstract
F-box and WD repeat domain containing 7 (FBXW7) acts as a substrate receptor of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and plays crucial roles in the regulation of several cellular processes, including cell growth, division, and differentiation, by targeting diverse key regulators for degradation. However, its role in regulating cellular senescence remains elusive. Here, we found that FBXW7 inactivation by siRNA-based knockdown or CRISPR/Cas9-based knockout induced significant cellular senescence in p53 wild-type cells, but not in p53 mutant or null cells, along with activation of both the p53/p21 and p16INK4a/Rb pathways. Simultaneous p53 inactivation abrogated senescence and cell growth arrest induced by FBXW7 deficiency as well as the alteration of both the p53/p21 and p16INK4a/Rb pathways. Moreover, Fbxw7 deletion accelerated replicative senescence of primary mouse embryonic fibroblasts in a p53-dependent manner. In addition, FBXW7 deletion induced the senescence-associated secretory phenotype to trigger secondary senescence. Importantly, in a radiation-induced senescence mouse model, simultaneous deletion of p53 rescued accelerated senescence and aging caused by Fbxw7 loss. Thus, our study uncovered a novel role for FBXW7 in the regulation of senescence by eliminating p53.
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18
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Arconada-Luque E, Jiménez-Suarez J, Pascual-Serra R, Nam-Cha SH, Moline T, Cimas FJ, Fliquete G, Ortega-Muelas M, Roche O, Fernández-Aroca DM, Muñoz Velasco R, García-Flores N, Garnés-García C, Sánchez-Fdez A, Matilla-Almazán S, Sánchez-Arévalo Lobo VJ, Hernández-Losa J, Belandia B, Pandiella A, Esparís-Ogando A, Ramón y Cajal S, del Peso L, Sánchez-Prieto R, Ruiz-Hidalgo MJ. ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology. Cancers (Basel) 2022; 14:cancers14143509. [PMID: 35884568 PMCID: PMC9316148 DOI: 10.3390/cancers14143509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/11/2022] [Accepted: 07/16/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Sarcoma is a heterogeneous group of tumors poorly studied with few therapeutic opportunities. Interestingly, the role of MAPKs still remains unclear in sarcomatous pathology. Here, we describe for the first time the critical role of ERK5 in the biology of soft tissue sarcoma by using in vitro and in vivo approaches in a murine experimental model of chemical sarcomagenesis. Indeed, our observations were extrapolated to a short series of human leiomyosarcoma and rhabdomyosarcomas. Furthermore, transcriptome analysis allows us to demonstrate the critical role of KLF2 in the biological effects of ERK5. Therefore, the data presented here open new windows in the diagnosis and therapy of soft tissue sarcomas. Abstract Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5–KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology.
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Affiliation(s)
- Elena Arconada-Luque
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
| | - Jaime Jiménez-Suarez
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
| | - Raquel Pascual-Serra
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
| | - Syong Hyun Nam-Cha
- Servicio de Anatomía Patológica, Hospital General de Albacete, 02008 Albacete, Spain;
| | - Teresa Moline
- Grupo de Patología Molecular Traslacional, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona Centro de Investigación Biomédica en RED de Cancer CIBERONC, 08035 Barcelona, Spain; (T.M.); (G.F.); (J.H.-L.); (S.R.y.C.)
| | - Francisco J. Cimas
- Unidad de Bioquímica y Biología Molecular, Servicio de Instrumentación Biomédica, Universidad de Castilla-La Mancha, 02008 Albacete, Spain;
| | - Germán Fliquete
- Grupo de Patología Molecular Traslacional, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona Centro de Investigación Biomédica en RED de Cancer CIBERONC, 08035 Barcelona, Spain; (T.M.); (G.F.); (J.H.-L.); (S.R.y.C.)
| | - Marta Ortega-Muelas
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
| | - Olga Roche
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
- Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Diego M. Fernández-Aroca
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
| | - Raúl Muñoz Velasco
- Grupo de Oncología Molecular, Facultad de Ciencias Experimentales, Instituto de Investigación Biosanitaria, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (R.M.V.); (V.J.S.-A.L.)
- Departamento de Anatomía Patológica, Instituto de Investigación Hospital 12 de Octubre, Av. Córdoba, s/n, 28041 Madrid, Spain
| | - Natalia García-Flores
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
| | - Cristina Garnés-García
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
| | - Adrián Sánchez-Fdez
- Instituto de Biología Molecular y Celular del Cáncer-CSIC, 37007 Salamanca, Spain; (A.S.-F.); (S.M.-A.); (A.P.); (A.E.-O.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, 37007 Salamanca, Spain
- Centro de Investigación Biomédica en RED de Cancer CIBERONC, 37007 Salamanca, Spain
| | - Sofía Matilla-Almazán
- Instituto de Biología Molecular y Celular del Cáncer-CSIC, 37007 Salamanca, Spain; (A.S.-F.); (S.M.-A.); (A.P.); (A.E.-O.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, 37007 Salamanca, Spain
- Centro de Investigación Biomédica en RED de Cancer CIBERONC, 37007 Salamanca, Spain
| | - Víctor J. Sánchez-Arévalo Lobo
- Grupo de Oncología Molecular, Facultad de Ciencias Experimentales, Instituto de Investigación Biosanitaria, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (R.M.V.); (V.J.S.-A.L.)
- Departamento de Anatomía Patológica, Instituto de Investigación Hospital 12 de Octubre, Av. Córdoba, s/n, 28041 Madrid, Spain
| | - Javier Hernández-Losa
- Grupo de Patología Molecular Traslacional, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona Centro de Investigación Biomédica en RED de Cancer CIBERONC, 08035 Barcelona, Spain; (T.M.); (G.F.); (J.H.-L.); (S.R.y.C.)
| | - Borja Belandia
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain;
| | - Atanasio Pandiella
- Instituto de Biología Molecular y Celular del Cáncer-CSIC, 37007 Salamanca, Spain; (A.S.-F.); (S.M.-A.); (A.P.); (A.E.-O.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, 37007 Salamanca, Spain
- Centro de Investigación Biomédica en RED de Cancer CIBERONC, 37007 Salamanca, Spain
| | - Azucena Esparís-Ogando
- Instituto de Biología Molecular y Celular del Cáncer-CSIC, 37007 Salamanca, Spain; (A.S.-F.); (S.M.-A.); (A.P.); (A.E.-O.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, 37007 Salamanca, Spain
- Centro de Investigación Biomédica en RED de Cancer CIBERONC, 37007 Salamanca, Spain
| | - Santiago Ramón y Cajal
- Grupo de Patología Molecular Traslacional, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona Centro de Investigación Biomédica en RED de Cancer CIBERONC, 08035 Barcelona, Spain; (T.M.); (G.F.); (J.H.-L.); (S.R.y.C.)
| | - Luis del Peso
- Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), 28029 Madrid, Spain;
- Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias CIBERES, 28029 Madrid, Spain
| | - Ricardo Sánchez-Prieto
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
- Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain;
- Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas (IIBM-CSIC)-Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Correspondence:
| | - María José Ruiz-Hidalgo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain; (E.A.-L.); (J.J.-S.); (R.P.-S.); (M.O.-M.); (O.R.); (D.M.F.-A.); (N.G.-F.); (C.G.-G.); (M.J.R.-H.)
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
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Shamsiya A, Pathoor R, Bahulayan D. Indole/oxazolone functionalized coumarins as pH-sensitive fluorescent kinase inhibitors. Tetrahedron Lett 2022. [DOI: 10.1016/j.tetlet.2022.153905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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20
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Andreu-Sánchez S, Aubert G, Ripoll-Cladellas A, Henkelman S, Zhernakova DV, Sinha T, Kurilshikov A, Cenit MC, Jan Bonder M, Franke L, Wijmenga C, Fu J, van der Wijst MGP, Melé M, Lansdorp P, Zhernakova A. Genetic, parental and lifestyle factors influence telomere length. Commun Biol 2022; 5:565. [PMID: 35681050 PMCID: PMC9184499 DOI: 10.1038/s42003-022-03521-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 05/22/2022] [Indexed: 11/09/2022] Open
Abstract
The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.
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Affiliation(s)
- Sergio Andreu-Sánchez
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
| | - Geraldine Aubert
- Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, BC, Canada
- Repeat Diagnostics Inc, Vancouver, BC, Canada
| | - Aida Ripoll-Cladellas
- Life Sciences Department, Barcelona Supercomputing Center, 08034, Barcelona, Catalonia, Spain
| | - Sandra Henkelman
- European Research Institute for the Biology of Ageing, University of Groningen, Groningen, the Netherlands
| | - Daria V Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St. Petersburg, 197101, Russia
| | - Trishla Sinha
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Alexander Kurilshikov
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Maria Carmen Cenit
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Microbial Ecology, Nutrition, and Health Research Unit, Institute of Agrochemistry and Food Technology (IATA-CSIC), 46980, Paterna-Valencia, Spain
| | - Marc Jan Bonder
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, Germany
| | - Lude Franke
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jingyuan Fu
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Monique G P van der Wijst
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marta Melé
- Life Sciences Department, Barcelona Supercomputing Center, 08034, Barcelona, Catalonia, Spain
| | - Peter Lansdorp
- Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, BC, Canada.
- European Research Institute for the Biology of Ageing, University of Groningen, Groningen, the Netherlands.
- Departments of Hematology and Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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21
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Zanotti S, Decaesteker B, Vanhauwaert S, De Wilde B, De Vos WH, Speleman F. Cellular senescence in neuroblastoma. Br J Cancer 2022; 126:1529-1538. [PMID: 35197583 PMCID: PMC9130206 DOI: 10.1038/s41416-022-01755-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 01/14/2022] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma is a tumour that arises from the sympathoadrenal lineage occurring predominantly in children younger than five years. About half of the patients are diagnosed with high-risk tumours and undergo intensive multi-modal therapy. The success rate of current treatments for high-risk neuroblastoma is disappointingly low and survivors suffer from multiple therapy-related long-term side effects. Most chemotherapeutics drive cancer cells towards cell death or senescence. Senescence has long been considered to represent a terminal non-proliferative state and therefore an effective barrier against tumorigenesis. This dogma, however, has been challenged by recent observations that infer a much more dynamic and reversible nature for this process, which may have implications for the efficacy of therapy-induced senescence-oriented treatment strategies. Neuroblastoma cells in a dormant, senescent-like state may escape therapy, whilst their senescence-associated secretome may promote inflammation and invasiveness, potentially fostering relapse. Conversely, due to its distinct molecular identity, senescence may also represent an opportunity for the development of novel (combination) therapies. However, the limited knowledge on the molecular dynamics and diversity of senescence signatures demands appropriate models to study this process in detail. This review summarises the molecular knowledge about cellular senescence in neuroblastoma and investigates current and future options towards therapeutic exploration.
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Affiliation(s)
- Sofia Zanotti
- grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, 2610 Belgium ,grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.510942.bCancer Research Institute Ghent (CRIG), Ghent, 9000 Belgium
| | - Bieke Decaesteker
- grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.510942.bCancer Research Institute Ghent (CRIG), Ghent, 9000 Belgium
| | - Suzanne Vanhauwaert
- grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.510942.bCancer Research Institute Ghent (CRIG), Ghent, 9000 Belgium
| | - Bram De Wilde
- grid.5342.00000 0001 2069 7798Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.5342.00000 0001 2069 7798Department of Internal Medicine and Pediatrics, Ghent University, Corneel Heymanslaan 10, Ghent, 9000 Belgium ,grid.410566.00000 0004 0626 3303Department of Pediatric Hematology Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, 9000 Belgium
| | - Winnok H. De Vos
- grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, Antwerp, 2610 Belgium
| | - Frank Speleman
- Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, Ghent, 9000, Belgium. .,Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
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22
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Abstract
Senescence is a cellular response to a variety of stress signals that is characterized by a stable withdrawal from the cell cycle and major changes in cell morphology and physiology. While most research on senescence has been performed on non-cancer cells, it is evident that cancer cells can also mount a senescence response. In this Review, we discuss how senescence can be induced in cancer cells. We describe the distinctive features of senescent cancer cells and how these changes in cellular physiology might be exploited for the selective eradication of these cells (senolysis). We discuss activation of the host immune system as a particularly attractive way to clear senescent cancer cells. Finally, we consider the challenges and opportunities provided by a 'one-two punch' sequential treatment of cancer with pro-senescence therapy followed by senolytic therapy.
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Affiliation(s)
- Liqin Wang
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Lina Lankhorst
- Cancer, Stem Cells & Developmental Biology programme, Utrecht University, Utrecht, The Netherlands
| | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
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23
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Tanaskovic N, Dalsass M, Filipuzzi M, Ceccotti G, Verrecchia A, Nicoli P, Doni M, Olivero D, Pasini D, Koseki H, Sabò A, Bisso A, Amati B. Polycomb group ring finger protein 6 suppresses Myc-induced lymphomagenesis. Life Sci Alliance 2022; 5:5/8/e202101344. [PMID: 35422437 PMCID: PMC9012912 DOI: 10.26508/lsa.202101344] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/04/2022] [Accepted: 04/04/2022] [Indexed: 12/15/2022] Open
Abstract
Max dimerizes with Mga to form the repressive complex PRC1.6; another PRC1.6 subunit, Pcgf6, suppresses Myc-induced lymphomagenesis but, unexpectedly, does so in a Mga- and PRC1.6-independent manner. Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4, and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6–but not Mga–accelerates Myc-induced lymphomagenesis in Eµ-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.
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Affiliation(s)
| | - Mattia Dalsass
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | | | | | | | - Paola Nicoli
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Mirko Doni
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Daniela Olivero
- Laboratorio Analisi Veterinarie BiEsseA, A Company of Scil Animal Care Company Srl, Milan, Italy
| | - Diego Pasini
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
- Department of Health Sciences, University of Milan, Milan, Italy
| | - Haruhiko Koseki
- Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Cellular and Molecular Medicine, Advanced Research Departments, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Arianna Sabò
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Andrea Bisso
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Bruno Amati
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
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24
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Cyclin-Dependent Kinase Synthetic Lethality Partners in DNA Damage Response. Int J Mol Sci 2022; 23:ijms23073555. [PMID: 35408915 PMCID: PMC8998982 DOI: 10.3390/ijms23073555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/16/2022] [Accepted: 03/23/2022] [Indexed: 02/07/2023] Open
Abstract
Cyclin-dependent kinases (CDKs) are pivotal mediators and effectors of the DNA damage response (DDR) that regulate both the pathway components and proteins involved in repair processes. Synthetic lethality (SL) describes a situation in which two genes are linked in such a way that the lack of functioning of just one maintains cell viability, while depletion of both triggers cell death. Synthetic lethal interactions involving CDKs are now emerging, and this can be used to selectively target tumor cells with DNA repair defects. In this review, SL interactions of CDKs with protooncogene products MYC, poly (ADP-ribose) polymerase (PARP-1), and cellular tumor antigen p53 (TP53) are discussed. The individual roles of each of the SL partners in DDR are described.
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25
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Hong X, Wang L, Zhang K, Liu J, Liu JP. Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis. Cells 2022; 11:877. [PMID: 35269498 PMCID: PMC8909789 DOI: 10.3390/cells11050877] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/04/2023] Open
Abstract
Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial stem cell senescence and senescence-associated differentiation disorders in pulmonary fibrosis, exploring the mechanisms mediating and preventing pulmonary fibrogenic crisis. Notably, the TGF-β signalling pathway mediates alveolar epithelial stem cell senescence by mechanisms involving suppression of the telomerase reverse transcriptase gene in pulmonary fibrosis. Alternatively, telomere uncapping caused by stress-induced telomeric shelterin protein TPP1 degradation mediates DNA damage response, pulmonary senescence and fibrosis. However, targeted intervention of cellular senescence disrupts pulmonary remodelling and fibrosis by clearing senescent cells using senolytics or preventing senescence using telomere dysfunction inhibitor (TELODIN). Studies indicate that the development of senescence-associated differentiation disorders is reprogrammable and reversible by inhibiting stem cell replicative senescence in pulmonary fibrosis, providing a framework for targeted intervention of the molecular mechanisms of alveolar stem cell senescence and pulmonary fibrosis. Abbreviations: DPS, developmental programmed senescence; IPF, idiopathic pulmonary fibrosis; OIS, oncogene-induced replicative senescence; SADD, senescence-associated differentiation disorder; SALI, senescence-associated low-grade inflammation; SIPS, stress-induced premature senescence; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci; TIS, therapy-induced senescence; VIS, virus-induced senescence.
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Affiliation(s)
- Xiaojing Hong
- Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China; (X.H.); (L.W.); (K.Z.); (J.L.)
| | - Lihui Wang
- Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China; (X.H.); (L.W.); (K.Z.); (J.L.)
| | - Kexiong Zhang
- Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China; (X.H.); (L.W.); (K.Z.); (J.L.)
| | - Jun Liu
- Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China; (X.H.); (L.W.); (K.Z.); (J.L.)
| | - Jun-Ping Liu
- Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China; (X.H.); (L.W.); (K.Z.); (J.L.)
- Department of Immunology and Pathology, Monash University Faculty of Medicine, Prahran, VIC 3181, Australia
- Hudson Institute of Medical Research, Monash University Department of Molecular and Translational Science, Clayton, VIC 3168, Australia
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26
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Murugan NJ, Voutsadakis IA. Proteasome regulators in pancreatic cancer. World J Gastrointest Oncol 2022; 14:38-54. [PMID: 35116102 PMCID: PMC8790418 DOI: 10.4251/wjgo.v14.i1.38] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/14/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
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Affiliation(s)
- Nirosha J Murugan
- Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada
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27
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Xie G, Peng Z, Liang J, Larabee SM, Drachenberg CB, Yfantis H, Raufman JP. Zinc finger protein 277 is an intestinal transit-amplifying cell marker and colon cancer oncogene. JCI Insight 2022; 7:150894. [PMID: 35015732 PMCID: PMC8876557 DOI: 10.1172/jci.insight.150894] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 01/05/2022] [Indexed: 01/10/2023] Open
Abstract
Sustained proliferative signaling and resisting cell death are hallmarks of cancer. Zinc finger protein 277 (ZNF277; murine Zfp277), a transcription factor regulating cellular senescence, is overexpressed in colon cancer, but its actions in intestinal homeostasis and neoplasia are unclear. Using human and murine intestine, human colon cancer cells, and ApcMin/+ mice with dysregulated β-catenin signaling and exuberant intestinal neoplasia, we explored the actions of ZNF277/Zfp277 and defined the underlying mechanisms. In normal human and murine intestine, ZNF277/Zfp277 was expressed uniquely in early stem cell progenitors, undifferentiated transit-amplifying cells (TACs). Zfp277 was overexpressed in the ApcMin/+ mouse colon, implicating ZNF277/Zfp277 as a transcriptional target of β-catenin signaling. We confirmed this by showing β-catenin knockdown reduced ZNF277 expression and, using chromatin IP, identified 2 β-catenin binding sites in the ZNF277 promoter. Zfp277 deficiency attenuated intestinal epithelial cell proliferation and tumor formation, and it strikingly prolonged ApcMin/+ mouse survival. RNA-Seq and PCR analyses revealed that Zfp277 modulates expression of genes in key cancer pathways, including β-catenin signaling, the HOXD family that regulates development, and p21WAF1, a cell cycle inhibitor and tumor suppressor. In both human colon cancer cells and the murine colon, ZNF277/Zfp277 deficiency induced p21WAF1 expression and promoted senescence. Our findings identify ZNF277/Zfp277 as both a TAC marker and colon cancer oncogene that regulates cellular proliferation and senescence, in part by repressing p21WAF1 expression.
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Affiliation(s)
- Guofeng Xie
- University of Maryland School of Medicine, Baltimore, United States of America
| | - Zhongsheng Peng
- Department of Medicine, University of Maryland School of Medicine, Baltimore, United States of America
| | - Jinqing Liang
- Department of Medicine, University of Maryland School of Medicine, Baltimore, United States of America
| | - Shannon M Larabee
- Department of Surgery, University of Maryland School of Medicine, Baltimore, United States of America
| | - Cinthia B Drachenberg
- Department of Pathology, University of Maryland School of Medicine, Baltimore, United States of America
| | - Harris Yfantis
- Department of Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, United States of America
| | - Jean-Pierre Raufman
- Department of Medicine, University of Maryland School of Medicine, Baltimore, United States of America
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28
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Ou H, Hoffmann R, González‐López C, Doherty GJ, Korkola JE, Muñoz‐Espín D. Cellular senescence in cancer: from mechanisms to detection. Mol Oncol 2021; 15:2634-2671. [PMID: 32981205 PMCID: PMC8486596 DOI: 10.1002/1878-0261.12807] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/25/2020] [Accepted: 09/22/2020] [Indexed: 01/10/2023] Open
Abstract
Senescence refers to a cellular state featuring a stable cell-cycle arrest triggered in response to stress. This response also involves other distinct morphological and intracellular changes including alterations in gene expression and epigenetic modifications, elevated macromolecular damage, metabolism deregulation and a complex pro-inflammatory secretory phenotype. The initial demonstration of oncogene-induced senescence in vitro established senescence as an important tumour-suppressive mechanism, in addition to apoptosis. Senescence not only halts the proliferation of premalignant cells but also facilitates the clearance of affected cells through immunosurveillance. Failure to clear senescent cells owing to deficient immunosurveillance may, however, lead to a state of chronic inflammation that nurtures a pro-tumorigenic microenvironment favouring cancer initiation, migration and metastasis. In addition, senescence is a response to post-therapy genotoxic stress. Therefore, tracking the emergence of senescent cells becomes pivotal to detect potential pro-tumorigenic events. Current protocols for the in vivo detection of senescence require the analysis of fixed or deep-frozen tissues, despite a significant clinical need for real-time bioimaging methods. Accuracy and efficiency of senescence detection are further hampered by a lack of universal and more specific senescence biomarkers. Recently, in an attempt to overcome these hurdles, an assortment of detection tools has been developed. These strategies all have significant potential for clinical utilisation and include flow cytometry combined with histo- or cytochemical approaches, nanoparticle-based targeted delivery of imaging contrast agents, OFF-ON fluorescent senoprobes, positron emission tomography senoprobes and analysis of circulating SASP factors, extracellular vesicles and cell-free nucleic acids isolated from plasma. Here, we highlight the occurrence of senescence in neoplasia and advanced tumours, assess the impact of senescence on tumorigenesis and discuss how the ongoing development of senescence detection tools might improve early detection of multiple cancers and response to therapy in the near future.
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Affiliation(s)
- Hui‐Ling Ou
- CRUK Cambridge Centre Early Detection ProgrammeDepartment of OncologyHutchison/MRC Research CentreUniversity of CambridgeUK
| | - Reuben Hoffmann
- Department of Biomedical EngineeringKnight Cancer InstituteOHSU Center for Spatial Systems BiomedicineOregon Health and Science UniversityPortlandORUSA
| | - Cristina González‐López
- CRUK Cambridge Centre Early Detection ProgrammeDepartment of OncologyHutchison/MRC Research CentreUniversity of CambridgeUK
| | - Gary J. Doherty
- Department of OncologyCambridge University Hospitals NHS Foundation TrustCambridge Biomedical CampusUK
| | - James E. Korkola
- Department of Biomedical EngineeringKnight Cancer InstituteOHSU Center for Spatial Systems BiomedicineOregon Health and Science UniversityPortlandORUSA
| | - Daniel Muñoz‐Espín
- CRUK Cambridge Centre Early Detection ProgrammeDepartment of OncologyHutchison/MRC Research CentreUniversity of CambridgeUK
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29
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Leu JD, Wang CY, Lo CC, Lin MY, Chang CY, Hung WC, Lin ST, Wang BS, Lee YJ. Involvement of c-Myc in low dose radiation-induced senescence enhanced migration and invasion of unirradiated cancer cells. Aging (Albany NY) 2021; 13:22208-22231. [PMID: 34552037 PMCID: PMC8507273 DOI: 10.18632/aging.203527] [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: 02/04/2021] [Accepted: 08/11/2021] [Indexed: 12/27/2022]
Abstract
Ionizing radiation is known to cause cell apoptosis at high dose range, but little is known about the cellular response to low dose radiation. In this study, we found that conditioned medium harvested from WI-38 lung fibroblasts and H1299 lung adenocarcinoma cells exposed to 0.1Gy to 1Gy could enhance the migration and invasion of unirradiated H1299 cells in both 2D and 3D culturing circumstances. Low dose radiation did not induce apoptosis, but induced senescence in irradiated cells. We next examined the expression of immediately early genes including c-Myc and K-Ras. Although both genes could be up-regulated by low dose radiation, induction of c-Myc was more specific to low dose range (0.5Gy) at transcriptional and translational levels. Knockdown of c-Myc by shRNA could repress the senescence induced by low dose radiation. The conditioned medium of irradiated cells induced migration of unirradiated cells was also repressed by knockdown of c-Myc. The c-Myc inhibitor 10058-F4 could suppress low dose radiation induced cell senescence, and the conditioned medium harvested from irradiated cells pretreated with 10058-F4 also lost the ability to enhance the migration of unirradiated cells. The cytokine array analysis revealed that immunosuppressive monocyte chemoattractant protein-1 increased by low dose radiation could be repressed by 10058-F4. We also showed that 10058-F4 could suppress low dose radiation induced tumor progression in a xenograft tumor model. Taken together, current data suggest that -Myc is involved in low dose radiation induced cell senescence and potent bystander effect to increase the motility of unirradiated cells.
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Affiliation(s)
- Jyh-Der Leu
- Department of Radiation Oncology, Taipei City Hospital, Taipei 110, Taiwan.,Institute of Neuroscience, National Cheng Chi University, Taipei 116, Taiwan
| | - Chung-Yih Wang
- Radiotherapy, Department of Medical Imaging, Cheng Hsin General Hospital, Taipei 112, Taiwan
| | - Chia-Chien Lo
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Min-Ying Lin
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Chun-Yuan Chang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.,Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903-2681, USA
| | - Wen-Chin Hung
- Department of Radiation Oncology, Taipei City Hospital, Taipei 110, Taiwan
| | - Shi-Ting Lin
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Bo-Shen Wang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Yi-Jang Lee
- Department of Radiation Oncology, Taipei City Hospital, Taipei 110, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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30
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Zanotti S, Vanhauwaert S, Van Neste C, Olexiouk V, Van Laere J, Verschuuren M, Van der Meulen J, Mus LM, Durinck K, Tilleman L, Deforce D, Van Nieuwerburgh F, Hogarty MD, Decaesteker B, De Vos WH, Speleman F. MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells. Sci Rep 2021; 11:14454. [PMID: 34262099 PMCID: PMC8280219 DOI: 10.1038/s41598-021-93863-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 07/01/2021] [Indexed: 12/25/2022] Open
Abstract
MYCN is an oncogenic driver in neural crest-derived neuroblastoma and medulloblastoma. To better understand the early effects of MYCN activation in a neural-crest lineage context, we profiled the transcriptome of immortalized human retina pigment epithelial cells with inducible MYCN activation. Gene signatures associated with elevated MYC/MYCN activity were induced after 24 h of MYCN activation, which attenuated but sustained at later time points. Unexpectedly, MYCN activation was accompanied by reduced cell growth. Gene set enrichment analysis revealed a senescence-like signature with strong induction of p53 and p21 but in the absence of canonical hallmarks of senescence such as β-galactosidase positivity, suggesting incomplete cell fate commitment. When scrutinizing the putative drivers of this growth attenuation, differential gene expression analysis identified several regulators of nucleolar stress. This process was also reflected by phenotypic correlates such as cytoplasmic granule accrual and nucleolar coalescence. Hence, we propose that the induction of MYCN congests the translational machinery, causing nucleolar stress and driving cells into a transient pre-senescent state. Our findings shed new light on the early events induced by MYCN activation and may help unravelling which factors are required for cells to tolerate unscheduled MYCN overexpression during early malignant transformation.
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Affiliation(s)
- Sofia Zanotti
- Laboratory of Cell Biology and Histology, Dept. Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
| | - Suzanne Vanhauwaert
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
| | - Christophe Van Neste
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
| | - Volodimir Olexiouk
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
| | - Jolien Van Laere
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
| | - Marlies Verschuuren
- Laboratory of Cell Biology and Histology, Dept. Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Joni Van der Meulen
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
- Molecular Diagnostic, Ghent University, 9000, Ghent, Belgium
| | - Liselot M Mus
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
- Bioresource Center Ghent, Health, Innovation and Research Center, Ghent University, Corneel Heymanslaan 10, 9000, Ghent, Belgium
| | - Kaat Durinck
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
| | - Laurentijn Tilleman
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
- Laboratory of Pharmaceutical Biotechnology, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium
| | - Dieter Deforce
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
- Laboratory of Pharmaceutical Biotechnology, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium
| | - Filip Van Nieuwerburgh
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
- Laboratory of Pharmaceutical Biotechnology, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium
| | - Michael D Hogarty
- Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Bieke Decaesteker
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium
| | - Winnok H De Vos
- Laboratory of Cell Biology and Histology, Dept. Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Frank Speleman
- Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
- Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium.
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Jhaveri K, Burris Rd HA, Yap TA, Hamilton E, Rugo HS, Goldman JW, Dann S, Liu F, Wong GY, Krupka H, Shapiro GI. The evolution of cyclin dependent kinase inhibitors in the treatment of cancer. Expert Rev Anticancer Ther 2021; 21:1105-1124. [PMID: 34176404 DOI: 10.1080/14737140.2021.1944109] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The cell cycle cyclin dependent kinases (CDKs) play a critical role in controlling the transition between cell cycle phases, as well as cellular transcription. Aberrant CDK activation is common in cancer, and deregulation of the cell cycle a key hallmark of cancer. Although CDK4/6 inhibitors are now a standard-of-care option for first- and second-line HR+HER2- metastatic breast cancer, resistance inevitably limits their clinical benefit. AREAS COVERED Early pan-CDK inhibitors targeted the cell cycle and RNA polymerase II phosphorylation, but were complicated by toxicity, providing a rationale and need for the development of selective CDK inhibitors. In this review, we highlight selected recent literature to provide a narrative review summarizing the current CDK inhibitor therapeutic landscape. We detail the challenges associated with targeting CDKs for the treatment of breast and other cancers and review emerging biomarkers that may aid response prediction. We also discuss the risk-benefit ratio for CDK therapy and explore promising combination approaches. EXPERT OPINION Although CDK inhibitors may stem the proliferation of cancer cells, resistance remains an issue, and currently there are limited biomarkers to predict response to therapy. Ongoing research investigating CDK inhibitors in cancer is of paramount importance to define appropriate and effective treatment regimens.
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Affiliation(s)
- Komal Jhaveri
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Howard A Burris Rd
- Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA
| | - Timothy A Yap
- The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Erika Hamilton
- Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA
| | - Hope S Rugo
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | | | | | | | | | | | - Geoffrey I Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Suski JM, Braun M, Strmiska V, Sicinski P. Targeting cell-cycle machinery in cancer. Cancer Cell 2021; 39:759-778. [PMID: 33891890 PMCID: PMC8206013 DOI: 10.1016/j.ccell.2021.03.010] [Citation(s) in RCA: 302] [Impact Index Per Article: 75.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/09/2021] [Accepted: 03/26/2021] [Indexed: 12/19/2022]
Abstract
Abnormal activity of the core cell-cycle machinery is seen in essentially all tumor types and represents a driving force of tumorigenesis. Recent studies revealed that cell-cycle proteins regulate a wide range of cellular functions, in addition to promoting cell division. With the clinical success of CDK4/6 inhibitors, it is becoming increasingly clear that targeting individual cell-cycle components may represent an effective anti-cancer strategy. Here, we discuss the potential of inhibiting different cell-cycle proteins for cancer therapy.
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Affiliation(s)
- Jan M Suski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Marcin Braun
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Chair of Oncology, Medical University of Lodz, 92-213 Lodz, Poland
| | - Vladislav Strmiska
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
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Chu C, Geng Y, Zhou Y, Sicinski P. Cyclin E in normal physiology and disease states. Trends Cell Biol 2021; 31:732-746. [PMID: 34052101 DOI: 10.1016/j.tcb.2021.05.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/29/2021] [Accepted: 05/03/2021] [Indexed: 01/17/2023]
Abstract
E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate cyclin-dependent kinase 2 (CDK2) and drive cell cycle progression by phosphorylating several cellular proteins. Abnormally elevated activity of cyclin E-CDK2 has been documented in many human tumor types. Moreover, cyclin E overexpression mediates resistance of tumor cells to various therapeutic agents. Recent work has revealed that the role of cyclin E extends well beyond cell proliferation and tumorigenesis, and it may regulate a diverse array of physiological and pathological processes. In this review, we discuss these various cyclin E functions and the potential for therapeutic targeting of cyclin E and cyclin E-CDK2 kinase.
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Affiliation(s)
- Chen Chu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yan Geng
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yu Zhou
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA; Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, China
| | - Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
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Ando K, Nakagawara A. Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy? Biomolecules 2021; 11:biom11050750. [PMID: 34069817 PMCID: PMC8157238 DOI: 10.3390/biom11050750] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/09/2021] [Accepted: 05/12/2021] [Indexed: 11/27/2022] Open
Abstract
Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.
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Affiliation(s)
- Kiyohiro Ando
- Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Saitama 362-0806, Japan
- Correspondence: (K.A.); (A.N.); Tel.: +81-48-722-1111 (K.A.); +81-942-50-8829 (A.N.)
| | - Akira Nakagawara
- Saga International Carbon Particle Beam Radiation Cancer Therapy Center, Saga HIMAT Foundation, 3049 Harakoga-Machi, Saga 841-0071, Japan
- Correspondence: (K.A.); (A.N.); Tel.: +81-48-722-1111 (K.A.); +81-942-50-8829 (A.N.)
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35
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Vásquez AF, González Barrios AF. Classical MD and metadynamics simulations on back-pocket binders of CDK2 and VEGFR2: a guidepost to design novel small-molecule dual inhibitors. J Biomol Struct Dyn 2021; 40:9030-9041. [PMID: 33949282 DOI: 10.1080/07391102.2021.1922311] [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] [Indexed: 12/14/2022]
Abstract
Cyclin-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are promising targets for the design of novel inhibitors in anticancer therapeutics. In a recent work, our group designed a set of potential dual inhibitors predicted to occupy an allosteric back pocket near the active site of both enzymes, but their dynamic and unbinding behavior was unclear. Here, we used molecular dynamics (MD) and metadynamics (meta-D) simulations to study two of these virtual candidates (herein called IQ2 and IQ3). Their binding mode was predicted to be similar to that observed in LQ5 and BAX, well-known back-pocket binders of CDK2 and VEGFR2, respectively, including H-bonding with critical residues such as Leu83/Cys113 and Asp145/Asp190 (but excepting H-bonding with Glu51/Glu111) in CDK2/VEGFR2, correspondingly. Likewise, while LQ5 and BAX unbound through the allosteric channel as expected for type-IIA inhibitors, IQ2 and IQ3 unbound via the ATP channel (except for CDK2-IQ2) as expected for type-I½A inhibitors. Interestingly, a C-C single/double bond difference between IQ2/IQ3, respectively, resulted associated with differences in the AS/T loop flexibility observed for CDK2. These insights will help developing scaffold modifications during an optimization stage, serving as a starting point to develop dual kinase inhibitors in challenging biological targets with a promising anticancer potential.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Andrés Felipe Vásquez
- Grupo de Diseño de Productos y Procesos (GDPP), Department of Chemical Engineering, Universidad de los Andes, Bogotá, Colombia
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Ramu D, Shan TW, Hirpara JL, Pervaiz S. Cellular senescence: Silent operator and therapeutic target in cancer. IUBMB Life 2021; 73:530-542. [PMID: 33675120 DOI: 10.1002/iub.2460] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 02/20/2021] [Accepted: 02/24/2021] [Indexed: 12/30/2022]
Abstract
The process of carcinogenesis and its progression involves an intricate interplay between a number of signaling networks, metabolic pathways and the microenvironment. These include an alteration in the cellular redox metabolism and deregulation of cell cycle checkpoints. Similar to the dichotomy of redox signaling in cancer cell fate and state determination, a diverging effect of an irreversible cell cycle arrest or senescence on carcinogenesis has been demonstrated. In this regard, while overwhelming oxidative stress has a damaging effect on tissue architecture and organ function and promotes death execution, a mild "pro-oxidant" environment is conducive for cell proliferation, growth and survival. Similarly, cellular senescence has been shown to elicit both a tumor suppressor and an oncogenic effect in a context-dependent manner. Notably, there appears to be a crosstalk between these two critical regulators of cell fate and state, particularly from the standpoint of the divergent effects on processes that promote or abate carcinogenesis. This review aims to provide an overview of these overarching themes and attempts to highlight critical intersection nodes, which are emerging as potential diagnostic and/or therapeutic targets for novel anticancer strategies.
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Affiliation(s)
- Deepika Ramu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Teoh Wei Shan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jayshree L Hirpara
- Cancer Science Institute, National University of Singapore, Singapore, Singapore
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,NUS Medicine Healthy Longevity Program, National University of Singapore, Singapore, Singapore.,National University Cancer Institute, National University Health System, Singapore, Singapore.,Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), National University of Singapore, Singapore, Singapore.,Faculté de Medicine, University of Paris, Paris, France
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37
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Schneeweis C, Hassan Z, Schick M, Keller U, Schneider G. The SUMO pathway in pancreatic cancer: insights and inhibition. Br J Cancer 2021; 124:531-538. [PMID: 33071285 PMCID: PMC7851129 DOI: 10.1038/s41416-020-01119-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 08/31/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022] Open
Abstract
An urgent medical need to develop novel treatment strategies for patients with pancreatic ductal adenocarcinoma (PDAC) exists. However, despite various efforts in the histopathological and molecular subtyping of PDAC, novel targeted or specific therapies have not been established. Posttranslational modifications (PTMs) with ubiquitin-like proteins, including small ubiquitin-like modifiers (SUMOs), mediate numerous processes that can contribute to the fitness and survival of cancer cells. The contribution of SUMOylation to transcriptional control, DNA repair pathways, mitotic progression, and oncogenic signalling has been described. Here we review functions of the SUMO pathway in PDAC, with a special focus on its connection to an aggressive subtype of the disease characterised by high MYC activity, and discuss SUMOylation inhibitors under development for precise PDAC therapies.
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Affiliation(s)
- Christian Schneeweis
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675, München, Germany
| | - Zonera Hassan
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675, München, Germany
| | - Markus Schick
- Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Ulrich Keller
- Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
- Max-Delbrück-Center for Molecular Medicine, 13092, Berlin, Germany.
| | - Günter Schneider
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675, München, Germany.
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
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Roupakia E, Markopoulos GS, Kolettas E. Genes and pathways involved in senescence bypass identified by functional genetic screens. Mech Ageing Dev 2021; 194:111432. [PMID: 33422562 DOI: 10.1016/j.mad.2021.111432] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 12/30/2020] [Accepted: 01/01/2021] [Indexed: 10/22/2022]
Abstract
Cellular senescence is a state of stable and irreversible cell cycle arrest with active metabolism, that normal cells undergo after a finite number of divisions (Hayflick limit). Senescence can be triggered by intrinsic and/or extrinsic stimuli including telomere shortening at the end of a cell's lifespan (telomere-initiated senescence) and in response to oxidative, genotoxic or oncogenic stresses (stress-induced premature senescence). Several effector mechanisms have been proposed to explain senescence programmes in diploid cells, including the induction of DNA damage responses, a senescence-associated secretory phenotype and epigenetic changes. Senescent cells display senescence-associated-β-galactosidase activity and undergo chromatin remodeling resulting in heterochromatinisation. Senescence is established by the pRb and p53 tumour suppressor networks. Senescence has been detected in in vitro cellular settings and in premalignant, but not malignant lesions in mice and humans expressing mutant oncogenes. Despite oncogene-induced senescence, which is believed to be a cancer initiating barrier and other tumour suppressive mechanisms, benign cancers may still develop into malignancies by bypassing senescence. Here, we summarise the functional genetic screens that have identified genes, uncovered pathways and characterised mechanisms involved in senescence evasion. These include cell cycle regulators and tumour suppressor pathways, DNA damage response pathways, epigenetic regulators, SASP components and noncoding RNAs.
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Affiliation(s)
- Eugenia Roupakia
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, Ioannina, 45100, Greece; Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, 45110, Greece
| | - Georgios S Markopoulos
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, Ioannina, 45100, Greece; Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, 45110, Greece
| | - Evangelos Kolettas
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, Ioannina, 45100, Greece; Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, 45110, Greece.
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Abstract
Cellular senescence plays a role in several physiological processes including aging, embryonic development, tissue remodeling, and wound healing and is considered one of the main barriers against tumor development. Studies of normal and tumor cells both in culture and in vivo suggest that MYC plays an important role in regulating senescence, thereby contributing to tumor development. We have previously described different common methods to measure senescence in cell cultures and in tissues. Unfortunately, there is no unique marker that unambiguously defines a senescent state, and it is therefore necessary to combine measurements of several different markers in order to assure the correct identification of senescent cells. Here we describe protocols for simultaneous detection of multiple senescence markers in situ, a quantitative fluorogenic method to measure senescence-associated β-galactosidase activity (SA-β-gal), and a new method to detect senescent cells based on the Sudan Black B (SBB) analogue GL13, which is applicable to formalin-fixed paraffin-embedded tissues. The application of these methods in various systems will hopefully shed further light on the role of MYC in regulation of senescence, and how that impacts normal physiological processes as well as diseases and in particular cancer development.
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Bazzar W, Bocci M, Hejll E, Högqvist Tabor V, Hydbring P, Grandien A, Alzrigat M, Larsson LG. Pharmacological inactivation of CDK2 inhibits MYC/BCL-XL-driven leukemia in vivo through induction of cellular senescence. Cell Cycle 2020; 20:23-38. [PMID: 33356836 PMCID: PMC7849765 DOI: 10.1080/15384101.2020.1855740] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Deregulated expression of the MYC oncogene is a frequent event during tumorigenesis and generally correlates with aggressive disease and poor prognosis. While MYC is a potent inducer of apoptosis, it often suppresses cellular senescence, which together with apoptosis is an important barrier against tumor development. For this latter function, MYC is dependent on cyclin-dependent kinase 2 (CDK2). Here, we utilized a MYC/BCL-XL-driven mouse model of acute myeloblastic leukemia (AML) to investigate whether pharmacological inhibition of CDK2 can inhibit MYC-driven tumorigenesis through induction of senescence. Purified mouse hematopoietic stem cells transduced with MYC and BCL-XL were transplanted into lethally irradiated mice, leading to the development of massive leukemia and subsequent death 15–17 days after transplantation. Upon disease onset, mice were treated with the selective CDK2 inhibitor CVT2584 or vehicle either by daily intraperitoneal injections or continuous delivery via mini-pumps. CVT2584 treatment delayed disease onset and moderately but significantly improved survival of mice. Flow cytometry revealed a significant decrease in tumor load in the spleen, liver and bone marrow of CVT2584-treated compared to vehicle-treated mice. This was correlated with induced senescence evidenced by reduced cell proliferation, increased senescence-associated β-galactosidase activity and heterochromatin foci, expression of p19ARF and p21CIP1, and reduced phosphorylation (activation) of pRb, while very few apoptotic cells were observed. In addition, phosphorylation of MYC at Ser-62 was decreased. In summary, inhibition of CDK2 delayed MYC/BCL-XL-driven AML linked to senescence induction. Our results suggest that CDK2 is a promising target for pro-senescence cancer therapy, in particular for MYC-driven tumors, including leukemia.
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Affiliation(s)
- Wesam Bazzar
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden
| | - Matteo Bocci
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden
| | - Eduar Hejll
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden
| | - Vedrana Högqvist Tabor
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden
| | - Per Hydbring
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden
| | - Alf Grandien
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital- Huddinge , Stockholm, Sweden
| | - Mohammad Alzrigat
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden
| | - Lars-Gunnar Larsson
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden
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Liu P, Tang Q, Chen M, Chen W, Lu Y, Liu Z, He Z. Hepatocellular Senescence: Immunosurveillance and Future Senescence-Induced Therapy in Hepatocellular Carcinoma. Front Oncol 2020; 10:589908. [PMID: 33330071 PMCID: PMC7732623 DOI: 10.3389/fonc.2020.589908] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The lack of effective targeted drugs has become a challenge on treating HCC patients. Cellular senescence is closely linked to the occurrence, development, and therapy of tumor. Induction of cellular senescence and further activation of immune surveillance provides a new strategy to develop HCC targeted drugs, that is, senescence-induced therapy for HCC. Precancerous hepatocytes or HCC cells can be induced into senescent cells, subsequently producing senescence-associated secretory phenotype (SASP) factors. SASP factors recruit and activate various types of immune cells, including T cells, NK cells, macrophages, and their subtypes, which carry out the role of immune surveillance and elimination of senescent cells, ultimately preventing the occurrence of HCC or inhibiting the progression of HCC. Specific interventions in several checkpoints of senescence-mediated therapy will make positive contributions to suppress tumorigenesis and progression of HCC, for instance, by applying small molecular compounds to induce cellular senescence or selecting cytokines/chemokines to activate immunosurveillance, supplementing adoptive immunocytes to remove senescent cells, and screening chemical drugs to induce apoptosis of senescent cells or accelerate clearance of senescent cells. These interventional checkpoints become potential chemotherapeutic targets in senescence-induced therapy for HCC. In this review, we focus on the frontiers of senescence-induced therapy and discuss senescent characteristics of hepatocytes during hepatocarcinogenesis as well as the roles and mechanisms of senescent cell induction and clearance, and cellular senescence-related immunosurveillance during the formation and progression of HCC.
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Affiliation(s)
- Peng Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Qinghe Tang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Miaomiao Chen
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Wenjian Chen
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Yanli Lu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Zhongmin Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
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42
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Jammal N, Rausch CR, Kadia TM, Pemmaraju N. Cell cycle inhibitors for the treatment of acute myeloid leukemia: a review of phase 2 & 3 clinical trials. Expert Opin Emerg Drugs 2020; 25:491-499. [PMID: 33161749 DOI: 10.1080/14728214.2020.1847272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Introduction: Acute myeloid leukemia (AML) is a clinically heterogeneous hematologic malignancy with poor long term outcomes. Cytotoxic chemotherapy remains the backbone of therapy especially among younger patients; however the effective incorporation of targeted therapies continues to be an area of active research in an effort to improve response durations and survival. Cell cycle inhibitors (CCI) are a novel class of agents which may be of particular interest for development in patients with AML. Areas covered: We will review the concept of CCIs along with available pre-clinical and clinical data in the treatment of AML both in North America and abroad. Specific drug targets reviewed include cyclin D kinase, Aurora kinase, CHK1, and WEE1. Expert opinion: Utilization of CCIs in patients with AML is an emerging approach that has shown promise in pre-clinical models. It has been challenging to translate this concept into clinical success thus far, due to marginal single-agent activity and significant toxicity profiles, however clinical evaluation is ongoing. Addition of these agents to cytotoxic chemotherapy and other targeted therapies provides a potential combinatorial path forward for this novel class of therapies. Developing optimal combinations while balancing toxicity are among the top clinical challenges that must be overcome before we can anticipate adoption of these agents into the armamentarium of AML therapy.
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Affiliation(s)
- Nadya Jammal
- Department of Leukemia, University of Texas, MD Anderson Cancer Center , Houston, Texas, USA
| | - Caitlin R Rausch
- Department of Leukemia, University of Texas, MD Anderson Cancer Center , Houston, Texas, USA
| | - Tapan M Kadia
- Department of Leukemia, University of Texas, MD Anderson Cancer Center , Houston, Texas, USA
| | - Naveen Pemmaraju
- Department of Leukemia, University of Texas, MD Anderson Cancer Center , Houston, Texas, USA
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FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping. Cell Metab 2020; 32:860-877.e9. [PMID: 33086033 DOI: 10.1016/j.cmet.2020.10.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 07/28/2020] [Accepted: 10/02/2020] [Indexed: 12/19/2022]
Abstract
Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.
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Chu X, Wen J, Raju RP. Rapid senescence-like response after acute injury. Aging Cell 2020; 19:e13201. [PMID: 32741083 PMCID: PMC7511876 DOI: 10.1111/acel.13201] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/11/2022] Open
Abstract
Cellular senescence is a state of irreversible growth arrest. Short‐term programmed senescence such as in embryonic development and slowly progressing senescence as in aging are both well described. However, acute senescence in living organisms is not well understood. We hypothesized that hemorrhagic shock injury (HI) caused by whole body hypoxia and nutrient deprivation, resulting in organ dysfunction due to severe blood loss, could lead to acute senescence in vivo. Our experiments, for the first time, demonstrate a rapidly emerged, senolytics‐responsive, senescence‐like response in the rat liver in less than five hr following hemorrhagic shock. We conclude that the senescence, or pseudosenescence, observed is necessary to maintain tissue homeostasis following the injury.
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Affiliation(s)
- Xiaogang Chu
- Department of Pharmacology and Toxicology Medical College of Georgia Augusta University Augusta GA USA
| | - Jin Wen
- Department of Pharmacology and Toxicology Medical College of Georgia Augusta University Augusta GA USA
| | - Raghavan Pillai Raju
- Department of Pharmacology and Toxicology Medical College of Georgia Augusta University Augusta GA USA
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms. Sci Rep 2020; 10:14149. [PMID: 32843692 PMCID: PMC7447758 DOI: 10.1038/s41598-020-70941-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 07/22/2020] [Indexed: 01/01/2023] Open
Abstract
The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
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46
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Kimata Y, Leturcq M, Aradhya R. Emerging roles of metazoan cell cycle regulators as coordinators of the cell cycle and differentiation. FEBS Lett 2020; 594:2061-2083. [PMID: 32383482 DOI: 10.1002/1873-3468.13805] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 01/10/2023]
Abstract
In multicellular organisms, cell proliferation must be tightly coordinated with other developmental processes to form functional tissues and organs. Despite significant advances in our understanding of how the cell cycle is controlled by conserved cell-cycle regulators (CCRs), how the cell cycle is coordinated with cell differentiation in metazoan organisms and how CCRs contribute to this process remain poorly understood. Here, we review the emerging roles of metazoan CCRs as intracellular proliferation-differentiation coordinators in multicellular organisms. We illustrate how major CCRs regulate cellular events that are required for cell fate acquisition and subsequent differentiation. To this end, CCRs employ diverse mechanisms, some of which are separable from those underpinning the conventional cell-cycle-regulatory functions of CCRs. By controlling cell-type-specific specification/differentiation processes alongside the progression of the cell cycle, CCRs enable spatiotemporal coupling between differentiation and cell proliferation in various developmental contexts in vivo. We discuss the significance and implications of this underappreciated role of metazoan CCRs for development, disease and evolution.
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Affiliation(s)
- Yuu Kimata
- School of Life Science and Technology, ShanghaiTech University, China
| | - Maïté Leturcq
- School of Life Science and Technology, ShanghaiTech University, China
| | - Rajaguru Aradhya
- School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala, India
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Neuropathology-driven Whole-genome Sequencing Study Points to Novel Candidate Genes for Healthy Brain Aging. Alzheimer Dis Assoc Disord 2020; 33:7-14. [PMID: 30681437 DOI: 10.1097/wad.0000000000000294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Understanding the healthy brain aging process is key to uncover the mechanisms that lead to pathologic age-related neurodegeneration, including progression to Alzheimer disease (AD). We aimed to address the issue of pathologic heterogeneity that often underlies a clinical AD diagnosis. METHODS We performed a deep whole-genome sequencing study aiming to identify variants that are associated specifically with healthy brain aging. PATIENTS We examined samples from the community-based longitudinal Vienna Transdanubian Aging study comparing neuropathologically "healthy" aging in individuals above 80 years of age with pure AD patients of the same age. RESULTS Focusing on potentially functional variants, we discovered a single variant (rs10149146) that lies on the autophagy-associated TECPR2 gene and was carried by 53.6% of the "healthy" brain elderly individuals (15/28). An additional nonsynonymous variant on the CINP gene (encoding a cell cycle checkpoint protein) was also found in 46% of healthy controls. Both variants are absent from all AD cases. TECPR2 and CINP appear to be "partner" genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. CONCLUSIONS Our study underlines the strength of neuropathology-driven definitions in genetic association studies and points to a potentially neuroprotective effect of key molecules of autophagy and cell cycle control.
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Qin A, Reddy HG, Weinberg FD, Kalemkerian GP. Cyclin-dependent kinase inhibitors for the treatment of lung cancer. Expert Opin Pharmacother 2020; 21:941-952. [PMID: 32164461 DOI: 10.1080/14656566.2020.1738385] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression in both normal and malignant cells, functioning through complex molecular interactions. Deregulation of CDK-dependent pathways is commonly found in both non-small cell and small cell lung cancer, and these derangements suggest vulnerabilities that can be exploited for clinical benefit. AREAS COVERED In this review, the authors present an overview of the biology of CDKs in normal and malignant cells, with a focus on lung cancer, followed by an assessment of preclinical work that has demonstrated the vital role of CDKs in lung cancer development and progression, and the activity of CDK inhibitors in a variety of lung cancer models. Finally, the experience with clinical trials of CDK inhibitors in lung cancer is discussed along with the current status of these agents in cancer therapy. EXPERT OPINION Despite strong biological rationale and promising preclinical studies, the results of clinical trials of CDK inhibitors in lung cancer have thus far been disappointing. Further clinical development of CDK inhibitors in lung cancer will depend on the identification of predictive biomarkers and the design of combination regimens that take advantage of the unique molecular alterations that drive lung cancer growth and survival.
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Affiliation(s)
- Angel Qin
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan , Ann Arbor, MI, USA
| | - Haritha G Reddy
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan , Ann Arbor, MI, USA
| | - Frank D Weinberg
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan , Ann Arbor, MI, USA
| | - Gregory P Kalemkerian
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan , Ann Arbor, MI, USA
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Vikramdeo KS, Saha P, Dutta S, Kumar N, Roy Chowdhury A, Kumar S, Tyagi RK, Ghosh I, Datta K. Hyaluronan-binding protein 1 (HABP1) overexpression triggers induction of senescence in fibroblasts cells. Cell Biol Int 2020; 44:1312-1330. [PMID: 32068317 DOI: 10.1002/cbin.11326] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 02/16/2020] [Indexed: 01/01/2023]
Abstract
Hyaluronan-binding protein 1 (HABP1), a multi-compartmental, multi-functional protein has a wide range of functions, which can be attributed to its ability to associate with a variety of cellular ligands. Earlier we have reported that HABP1 overexpression in rat normal fibroblasts (F-HABP07) shows chronic generation of reactive oxygen species (ROS), induction of autophagy, and apoptosis. However, a significant proportion of cells remained viable after the majority went through apoptosis from 60 to 72 h. In this study, an attempt has been made to delineate the cellular events in the declined population of surviving cells. It has been elucidated here that, these cells at later time points of growth, that is, 72 and 84 h, not only appeared to shrink but also are devoid of autophagic vacuoles and displayed polyploidy. F-HABP07 cells exhibited an altered cytoskeletal structure from their parental cell line F111, assumed to be caused upon inhibition of actin polymerization and decrease in IQ motif-containing GTPase activating protein 1 (IQGAP1), a key protein associated with maintenance of cytoskeletal integrity. Enhanced expression and nuclear localization of AKT observed in F-HABP07 cells appears to be contributing toward the maintenance of high ROS levels in these cells and also potentially modulating the IQGAP1 activity. These observations, in fact have been considered to result in sustained DNA damage, which then leads to increased expression of p53 and activation of p21 and carry out the cellular events responsible for senescence. Subsequent assessment of the presence of positive β-gal staining and enhanced expression of p16INK4a in F-HABP07, confirmed that HABP1 overexpressing fibroblasts undergo senescence.
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Affiliation(s)
- Kunwar Somesh Vikramdeo
- Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Paramita Saha
- Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.,Molecular Endocrinology Laboratory, Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Shubhra Dutta
- Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Naveen Kumar
- Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Anindya Roy Chowdhury
- Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Sudhir Kumar
- Molecular Endocrinology Laboratory, Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Rakesh Kumar Tyagi
- Molecular Endocrinology Laboratory, Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Ilora Ghosh
- Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Kasturi Datta
- Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
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50
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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: 39] [Impact Index Per Article: 6.5] [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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