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1
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Handa S, Puri S, Chatterjee M, Puri V. Bioinformatics-Driven Investigations of Signature Biomarkers for Triple-Negative Breast Cancer. Bioinform Biol Insights 2025; 19:11779322241271565. [PMID: 40034579 PMCID: PMC11873876 DOI: 10.1177/11779322241271565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 06/29/2024] [Indexed: 03/05/2025] Open
Abstract
Breast cancer is a highly heterogeneous disorder characterized by dysregulated expression of number of genes and their cascades. It is one of the most common types of cancer in women posing serious health concerns globally. Recent developments and discovery of specific prognostic biomarkers have enabled its application toward developing personalized therapies. The basic premise of this study was to investigate key signature genes and signaling pathways involved in triple-negative breast cancer using bioinformatics approach. Microarray data set GSE65194 from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus was used for identification of differentially expressed genes (DEGs) using R software. Gene ontology and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses were carried out using the ClueGO plugin in Cytoscape software. The up-regulated DEGs were primarily engaged in the regulation of cell cycle, overexpression of spindle assembly checkpoint, and so on, whereas down-regulated DEGs were employed in alteration to major signaling pathways and metabolic reprogramming. The hub genes were identified using cytoHubba from protein-protein interaction (PPI) network for top up-regulated and down-regulated DEG's plugin in Cytoscape software. The hub genes were validated as potential signature biomarkers by evaluating the overall survival percentage in breast cancer patients.
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Affiliation(s)
- Shristi Handa
- Biotechnology Engineering, University Institute of Engineering and Technology, Panjab University, Chandigarh, India
| | - Sanjeev Puri
- Biotechnology Engineering, University Institute of Engineering and Technology, Panjab University, Chandigarh, India
| | - Mary Chatterjee
- Biotechnology Engineering, University Institute of Engineering and Technology, Panjab University, Chandigarh, India
| | - Veena Puri
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India
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2
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Ashi A, Awaji AA, Bond J, Johnson CA, Shaaban AM, Bell SM. Threonine and tyrosine kinase (TTK) mRNA and protein expression in breast cancer; prognostic significance in the neoadjuvant setting. Histopathology 2025. [PMID: 39775836 DOI: 10.1111/his.15399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/04/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025]
Abstract
AIMS Threonine and tyrosine kinase (TTK) is up-regulated in triple-negative breast cancer (TNBC), yet its expression in patients undergoing neoadjuvant chemotherapy (NACT) remains unexplored. This investigation aims to assess TTK protein expression in treatment-naïve pre-treatment cores and paired pre- and post-NACT breast cancer (BC) cohorts, as well as its correlation with microcephaly 1 (MCPH1) protein expression. METHODS AND RESULTS Transcriptomic data were sourced from the Gene Expression Omnibus microarray database for mRNA expression analysis. TTK protein expression was evaluated using immunohistochemistry staining, employing receiver operating characteristic curve analysis to determine an optimal TTK expression cut-off point. The association between TTK expression, clinicopathological parameters and survival outcomes was examined. Additionally, MCPH1 protein expression was assessed in a pilot study. Analysis revealed a significantly elevated TTK mRNA expression in BC tissue compared to normal breast tissue, with high TTK mRNA levels predicting reduced overall survival. Notably, TTK protein expression increased significantly post-NACT in a paired cohort. Conversely, decreased TTK protein expression pre-NACT was correlated with improved overall survival. CONCLUSIONS High TTK and low MCPH1 protein expression was significantly correlated, highlighting TTK's potential as a biomarker for BC and a therapeutic target for MCPH1-deficient cancer cells.
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Affiliation(s)
- Abrar Ashi
- Division of Molecular Medicine, Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Aeshah A Awaji
- Division of Molecular Medicine, Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Jacquelyn Bond
- Division of Molecular Medicine, Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Colin A Johnson
- Division of Molecular Medicine, Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Abeer M Shaaban
- Histopathology, St James's Institute for Oncology, St James's University Hospital, Leeds, UK
- Histopathology and Cancer Sciences, Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, UK
| | - Sandra M Bell
- Division of Molecular Medicine, Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
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3
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Zhang S, Ding H, Deng Y, Ren Y, Zhou F, Zhang Q, Liu S. TTK promotes HER2 + breast cancer cell migration, apoptosis, and resistance to targeted therapy by modulating the Akt/mTOR axis. J Cancer Res Clin Oncol 2024; 150:512. [PMID: 39589549 PMCID: PMC11599621 DOI: 10.1007/s00432-024-06021-9] [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: 10/05/2024] [Accepted: 10/27/2024] [Indexed: 11/27/2024]
Abstract
BACKGROUND HER2 + breast cancer is a malignant neoplasm with a high degree of aggressiveness and therapeutic challenge. In recent years, studies have indicated a strong correlation between TTK and various tumors, though its role in HER2 + BRCA remains unclear. OBJECTIVES Studying the biological function of the TTK gene in HER2 + BRCA and its resistance to targeted therapy it provides new ideas for targeted drug research. METHODS TTK was knocked down by small interfering RNA transfection, and its biological function in HER2 + BRCA cells was verified, and its mechanism of action was verified by RT-PCR and Western blot. RESULTS The study demonstrated that TTK promoted cell proliferation and migration by activating the Akt/mTOR pathway in HER2 + breast cancer and enhanced the drug sensitivity of BRCA cell lines SKBR3 and BT474 to pyrotinib, in addition, knockdown of TTK induced apoptosis and arrested cells in G1 phase. CONCLUSION Which implies that TTK is an oncogene in HER2 + BRCA and is a valuable research target.
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Affiliation(s)
- Shaolin Zhang
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
- Department of General Surgery, Dejiang County People's Hospital, Tongren, Guizhou, China
| | - Hua Ding
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yongfen Deng
- Department of Cardiology, Dejiang County People's Hospital, Tongren, Guizhou, China
| | - Yu Ren
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Fulin Zhou
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
- Department of Breast Surgery, GuiYang Maternal and Child Health Care Hospital, Guiyang, China
| | - Qian Zhang
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Shu Liu
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China.
- Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
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4
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Rymuza J, Kober P, Maksymowicz M, Nyc A, Mossakowska BJ, Woroniecka R, Maławska N, Grygalewicz B, Baluszek S, Zieliński G, Kunicki J, Bujko M. High level of aneuploidy and recurrent loss of chromosome 11 as relevant features of somatotroph pituitary tumors. J Transl Med 2024; 22:994. [PMID: 39497133 PMCID: PMC11536836 DOI: 10.1186/s12967-024-05736-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 10/06/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Somatotroph neuroendocrine pituitary tumors (sPitNET) are a subtype of pituitary tumors that commonly cause acromegaly. Our study aimed to determine the spectrum of DNA copy number abnormalities (CNAs) in sPitNETs and their relevance. METHODS A landscape of CNAs in sPitNETs was determined using combined whole-genome approaches involving low-pass whole genome sequencing and SNP microarrays. Fluorescent in situ hybridization (FISH) was used for microscopic validation of CNAs. The tumors were also subjected to transcriptome and DNA methylation analyses with RNAseq and microarrays, respectively. RESULTS We observed a wide spectrum of cytogenetic changes ranging from multiple deletions, recurrent chromosome 11 loss, stable genomes, to duplication of the majority of the chromosomes. The identified CNAs were confirmed with FISH. sPitNETs with multiple duplications were characterized by intratumoral heterogeneity in chromosome number variation in individual tumor cells, as determined with FISH. These tumors were separate CNA-related sPitNET subtype in clustering analyses with CNA signature specific for whole genome doubling-related etiology. This subtype encompassed GNAS-wild type, mostly densely granulated tumors with favorable expression level of known prognosis-related genes, notably enriched with POUF1/NR5A1-double positive PitNETs. Chromosomal deletions in sPitNETs are functionally relevant. They occurred in gene-dense DNA regions and were related to genes downregulation and increased DNA methylation in the CpG island and promoter regions in the affected regions. Recurrent loss of chromosome 11 was reflected by lowered MEN1 and AIP. No such unequivocal relevance was found for chromosomal gains. Comparisons of transcriptomes of selected most cytogenetically stable sPitNETs with tumors with recurrent loss of chromosome 11 showed upregulation of processes related to gene dosage compensation mechanism in tumors with deletion. Comparison of stable tumors with those with multiple duplications showed upregulation of processes related to mitotic spindle, DNA repair, and chromatin organization. Both comparisons showed upregulation of the processes related to immune infiltration in cytogenetically stable tumors and deconvolution of DNA methylation data indicated a higher content of specified immune cells and lower tumor purity in these tumors. CONCLUSIONS sPitNETs fall into three relevant cytogenetic groups: highly aneuploid tumors characterized by known prognostically favorable features and low aneuploidy tumors including specific subtype with chromosome 11 loss.
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Affiliation(s)
- Julia Rymuza
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Paulina Kober
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Maria Maksymowicz
- Department of Cancer Pathomorphology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Aleksandra Nyc
- Department of Cancer Pathomorphology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata J Mossakowska
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Renata Woroniecka
- Cytogenetic Laboratory, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Natalia Maławska
- Cytogenetic Laboratory, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata Grygalewicz
- Cytogenetic Laboratory, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Szymon Baluszek
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Grzegorz Zieliński
- Department of Neurosurgery, Military Institute of Medicine, National Institute of Medicine, Warsaw, Poland
| | - Jacek Kunicki
- Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Mateusz Bujko
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
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Zanini E, Forster-Gross N, Bachmann F, Brüngger A, McSheehy P, Litherland K, Burger K, Groner AC, Roceri M, Bury L, Stieger M, Willemsen-Seegers N, de Man J, Vu-Pham D, van Riel HWE, Zaman GJR, Buijsman RC, Kellenberger L, Lane HA. Dual TTK/PLK1 inhibition has potent anticancer activity in TNBC as monotherapy and in combination. Front Oncol 2024; 14:1447807. [PMID: 39184047 PMCID: PMC11341980 DOI: 10.3389/fonc.2024.1447807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
Background Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891). Methods Mechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC). Results BAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent. Conclusions Dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.
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Affiliation(s)
- Elisa Zanini
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | | | - Felix Bachmann
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | - Adrian Brüngger
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | - Paul McSheehy
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | | | - Karin Burger
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | - Anna C. Groner
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | - Mila Roceri
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | - Luc Bury
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | - Martin Stieger
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
| | | | - Jos de Man
- Crossfire Oncology B.V., Oss, Netherlands
| | | | | | | | | | | | - Heidi A. Lane
- Basilea Pharmaceutica International Ltd, Allschwil, Switzerland
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Liang C, Zhou Y, Xin L, Kang K, Tian L, Zhang D, Li H, Zhao Q, Gao H, Shi Z. Hijacking monopolar spindle 1 (MPS1) for various cancer types by small molecular inhibitors: Deep insights from a decade of research and patents. Eur J Med Chem 2024; 273:116504. [PMID: 38795520 DOI: 10.1016/j.ejmech.2024.116504] [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: 02/29/2024] [Revised: 05/03/2024] [Accepted: 05/13/2024] [Indexed: 05/28/2024]
Abstract
Monopolar spindle 1 (MPS1) has garnered significant attention due to its pivotal role in regulating the cell cycle. Anomalous expression and hyperactivation of MPS1 have been associated with the onset and advancement of diverse cancers, positioning it as a promising target for therapeutic interventions. This review focuses on MPS1 small molecule inhibitors from the past decade, exploring design strategies, structure-activity relationships (SAR), safety considerations, and clinical performance. Notably, we propose prospects for MPS1 degraders based on proteolysis targeting chimeras (PROTACs), as well as reversible covalent bonding as innovative MPS1 inhibitor design strategies. The objective is to provide valuable information for future development and novel perspectives on potential MPS1 inhibitors.
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Affiliation(s)
- Chengyuan Liang
- School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China.
| | - Ying Zhou
- School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China
| | - Liang Xin
- School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China
| | - Kairui Kang
- School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China
| | - Lei Tian
- Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China; College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science& Technology, Xi'an, 710021, China
| | - Dezhu Zhang
- Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China; Shaanxi Panlong Pharmaceutical Group Co., Ltd., Xi'an, 710025, China
| | - Han Li
- School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Shaanxi Pioneer Biotech Co., Ltd., Xi'an, 710082, China
| | - Qianqian Zhao
- School of Biological and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an, 710021, China; Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China
| | - Hong Gao
- Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Research of Xi'an, Xi'an, 710021, China; Shaanxi Pioneer Biotech Co., Ltd., Xi'an, 710082, China
| | - Zhenfeng Shi
- Department of Urology Surgery Center, The People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, 830002, China
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Aquino-Acevedo AN, Orengo-Orengo JA, Cruz-Robles ME, Saavedra HI. Mitotic kinases are emerging therapeutic targets against metastatic breast cancer. Cell Div 2024; 19:21. [PMID: 38886738 PMCID: PMC11184769 DOI: 10.1186/s13008-024-00125-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 06/10/2024] [Indexed: 06/20/2024] Open
Abstract
This review aims to outline mitotic kinase inhibitors' roles as potential therapeutic targets and assess their suitability as a stand-alone clinical therapy or in combination with standard treatments for advanced-stage solid tumors, including triple-negative breast cancer (TNBC). Breast cancer poses a significant global health risk, with TNBC standing out as the most aggressive subtype. Comprehending the role of mitosis is crucial for understanding how TNBC advances from a solid tumor to metastasis. Chemotherapy is the primary treatment used to treat TNBC. Some types of chemotherapeutic agents target cells in mitosis, thus highlighting the need to comprehend the molecular mechanisms governing mitosis in cancer. This understanding is essential for devising targeted therapies to disrupt these mitotic processes, prevent or treat metastasis, and improve patient outcomes. Mitotic kinases like Aurora kinase A, Aurora Kinase B, never in mitosis gene A-related kinase 2, Threonine-Tyrosine kinase, and Polo-kinase 1 significantly impact cell cycle progression by contributing to chromosome separation and centrosome homeostasis. When these kinases go awry, they can trigger chromosome instability, increase cell proliferation, and activate different molecular pathways that culminate in a transition from epithelial to mesenchymal cells. Ongoing clinical trials investigate various mitotic kinase inhibitors as potential biological treatments against advanced solid tumors. While clinical trials against mitotic kinases have shown some promise in the clinic, more investigation is necessary, since they induce severe adverse effects, particularly affecting the hematopoietic system.
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Affiliation(s)
- Alexandra N Aquino-Acevedo
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA
| | - Joel A Orengo-Orengo
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA
| | - Melanie E Cruz-Robles
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA
| | - Harold I Saavedra
- Department of Basic Sciences, Ponce Health Sciences University-Ponce Research Institute, 388 Luis Salas Zona Industrial Reparada 2, P.O. Box 7004, Ponce, Puerto Rico, 00716-2347, USA.
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Hosea R, Hillary S, Naqvi S, Wu S, Kasim V. The two sides of chromosomal instability: drivers and brakes in cancer. Signal Transduct Target Ther 2024; 9:75. [PMID: 38553459 PMCID: PMC10980778 DOI: 10.1038/s41392-024-01767-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/18/2024] [Accepted: 02/06/2024] [Indexed: 04/02/2024] Open
Abstract
Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule-kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the "just-right" model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.
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Affiliation(s)
- Rendy Hosea
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Sharon Hillary
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Sumera Naqvi
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Shourong Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China.
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China.
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China.
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China.
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9
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Naik A, Lattab B, Qasem H, Decock J. Cancer testis antigens: Emerging therapeutic targets leveraging genomic instability in cancer. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200768. [PMID: 38596293 PMCID: PMC10876628 DOI: 10.1016/j.omton.2024.200768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Cancer care has witnessed remarkable progress in recent decades, with a wide array of targeted therapies and immune-based interventions being added to the traditional treatment options such as surgery, chemotherapy, and radiotherapy. However, despite these advancements, the challenge of achieving high tumor specificity while minimizing adverse side effects continues to dictate the benefit-risk balance of cancer therapy, guiding clinical decision making. As such, the targeting of cancer testis antigens (CTAs) offers exciting new opportunities for therapeutic intervention of cancer since they display highly tumor specific expression patterns, natural immunogenicity and play pivotal roles in various biological processes that are critical for tumor cellular fitness. In this review, we delve deeper into how CTAs contribute to the regulation and maintenance of genomic integrity in cancer, and how these mechanisms can be exploited to specifically target and eradicate tumor cells. We review the current clinical trials targeting aforementioned CTAs, highlight promising pre-clinical data and discuss current challenges and future perspectives for future development of CTA-based strategies that exploit tumor genomic instability.
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Affiliation(s)
- Adviti Naik
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Boucif Lattab
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Hanan Qasem
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
- College of Health and Life Sciences (CHLS), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, Qatar
| | - Julie Decock
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
- College of Health and Life Sciences (CHLS), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, Qatar
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10
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Pati D. Role of chromosomal cohesion and separation in aneuploidy and tumorigenesis. Cell Mol Life Sci 2024; 81:100. [PMID: 38388697 PMCID: PMC10884101 DOI: 10.1007/s00018-024-05122-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/28/2023] [Accepted: 01/09/2024] [Indexed: 02/24/2024]
Abstract
Cell division is a crucial process, and one of its essential steps involves copying the genetic material, which is organized into structures called chromosomes. Before a cell can divide into two, it needs to ensure that each newly copied chromosome is paired tightly with its identical twin. This pairing is maintained by a protein complex known as cohesin, which is conserved in various organisms, from single-celled ones to humans. Cohesin essentially encircles the DNA, creating a ring-like structure to handcuff, to keep the newly synthesized sister chromosomes together in pairs. Therefore, chromosomal cohesion and separation are fundamental processes governing the attachment and segregation of sister chromatids during cell division. Metaphase-to-anaphase transition requires dissolution of cohesins by the enzyme Separase. The tight regulation of these processes is vital for safeguarding genomic stability. Dysregulation in chromosomal cohesion and separation resulting in aneuploidy, a condition characterized by an abnormal chromosome count in a cell, is strongly associated with cancer. Aneuploidy is a recurring hallmark in many cancer types, and abnormalities in chromosomal cohesion and separation have been identified as significant contributors to various cancers, such as acute myeloid leukemia, myelodysplastic syndrome, colorectal, bladder, and other solid cancers. Mutations within the cohesin complex have been associated with these cancers, as they interfere with chromosomal segregation, genome organization, and gene expression, promoting aneuploidy and contributing to the initiation of malignancy. In summary, chromosomal cohesion and separation processes play a pivotal role in preserving genomic stability, and aberrations in these mechanisms can lead to aneuploidy and cancer. Gaining a deeper understanding of the molecular intricacies of chromosomal cohesion and separation offers promising prospects for the development of innovative therapeutic approaches in the battle against cancer.
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Affiliation(s)
- Debananda Pati
- Texas Children's Cancer Center, Department of Pediatrics Hematology/Oncology, Molecular and Cellular Biology, Baylor College of Medicine, 1102 Bates Avenue, Houston, TX, 77030, USA.
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11
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Du H, Zhang L, Chen J, Chen X, Qiang R, Ding X, Wang Y, Yang X. Upregulation of TTK expression is associated with poor prognosis and immune infiltration in endometrial cancer patients. Cancer Cell Int 2024; 24:20. [PMID: 38195567 PMCID: PMC10775523 DOI: 10.1186/s12935-023-03192-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/25/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND Threonine and tyrosine kinase (TTK) is associated with invasion and metastasis in various tumors. However, the prognostic importance of TTK and its correlation with immune infiltration in endometrial cancer (EC) remain unclear. METHODS The expression profile of TTK was analyzed using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteome Cancer Analysis Consortium (CPTAC). TTK protein and mRNA levels were verified in EC cell lines. Receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of TTK to distinguish between normal and EC tissues. K-M survival analysis was also conducted to evaluate the impact of TTK on survival outcomes. Protein‒protein interaction (PPI) networks associated with TTK were explored using the STRING database. Functional enrichment analysis was performed to elucidate the biological functions of TTK. TTK mRNA expression and immune infiltration correlations were examined using the Tumor Immune Estimation Resource (TIMER) and the Tumor-Immune System Interaction Database (TISIDB). RESULTS TTK expression was significantly greater in EC tissues than in adjacent normal tissues. Higher TTK mRNA expression was associated with tumor metastasis and advanced TNM stage. The protein and mRNA expression of TTK was significantly greater in tumor cell lines than in normal endometrial cell lines. ROC curve analysis revealed high accuracy (94.862%), sensitivity (95.652%), and specificity (94.894%) of TTK in differentiating EC from normal tissues. K-M survival analysis demonstrated that patients with high TTK expression had worse overall survival (OS) and disease-free survival (DFS) rates. Correlation analysis revealed that TTK mRNA expression was correlated with B cells and neutrophils. CONCLUSION TTK upregulation is significantly associated with poor survival outcomes and immune infiltration in patients with EC. TTK can serve as a potential biomarker for poor prognosis and a promising immunotherapy target in EC. Further investigation of the role of TTK in EC may provide valuable insights for therapeutic interventions and personalized treatment strategies.
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Affiliation(s)
- Hongxiang Du
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Li Zhang
- Department of Cancer Research Center, Nantong Tumor Hospital, The Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Jia Chen
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Department of Gynaecology and Obstetrics, JiangSu XiangShui Hospital of Chinese Medicine, XiangShui, China
| | - Xinyi Chen
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Ronghui Qiang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Xiaoyi Ding
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Yilang Wang
- Department of Oncology, The Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, China.
| | - Xiaoqing Yang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
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12
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Fuentes‐Antrás J, Bedard PL, Cescon DW. Seize the engine: Emerging cell cycle targets in breast cancer. Clin Transl Med 2024; 14:e1544. [PMID: 38264947 PMCID: PMC10807317 DOI: 10.1002/ctm2.1544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/10/2023] [Accepted: 12/31/2023] [Indexed: 01/25/2024] Open
Abstract
Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti-cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. These targets play critical roles in regulating quiescence, DNA replication and chromosome segregation. Extensive preclinical data support their potential to overcome CDK4/6 inhibitor resistance, induce synthetic lethality or sensitise tumours to immune checkpoint inhibitors. This review provides a biological and drug development perspective on emerging cell cycle targets and novel inhibitors, many of which exhibit favourable safety profiles and promising activity in clinical trials.
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Affiliation(s)
- Jesús Fuentes‐Antrás
- Division of Medical Oncology and HematologyDepartment of MedicinePrincess Margaret Cancer CentreUniversity Health NetworkUniversity of TorontoTorontoOntarioCanada
- NEXT OncologyHospital Universitario QuironSalud MadridMadridSpain
| | - Philippe L. Bedard
- Division of Medical Oncology and HematologyDepartment of MedicinePrincess Margaret Cancer CentreUniversity Health NetworkUniversity of TorontoTorontoOntarioCanada
| | - David W. Cescon
- Division of Medical Oncology and HematologyDepartment of MedicinePrincess Margaret Cancer CentreUniversity Health NetworkUniversity of TorontoTorontoOntarioCanada
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13
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Zeng Y, Ren X, Jin P, Zhang Y, Zhuo M, Wang J. Development of MPS1 Inhibitors: Recent Advances and Perspectives. J Med Chem 2023; 66:16484-16514. [PMID: 38095579 DOI: 10.1021/acs.jmedchem.3c00963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Monopolar spindle kinase 1 (MPS1) plays a pivotal role as a dual-specificity kinase governing spindle assembly checkpoint activation and sister chromatid separation in mitosis. Its overexpression has been observed in various human malignancies. MPS1 reduces spindle assembly checkpoint sensitivity, allowing tumor cells with a high degree of aneuploidy to complete mitosis and survive. Thus, MPS1 has emerged as a promising candidate for cancer therapy. Despite the identification of numerous MPS1 inhibitors, only five have advanced to clinical trials with none securing FDA approval for cancer treatment. In this perspective, we provide a concise overview of the structural and functional characteristics of MPS1 by highlighting its relevance to cancer. Additionally, we explore the structure-activity relationships, selectivity, and pharmacokinetics of MPS1 inhibitors featuring diverse scaffolds. Moreover, we review the reported work on enhancing MPS1 inhibitor selectivity, offering valuable insights into the discovery of novel, highly potent small-molecule MPS1 inhibitors.
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Affiliation(s)
- Yangjie Zeng
- Medical College, Guizhou University, Guiyang, Guizhou 550025, China
| | - Xiaodong Ren
- Medical College, Guizhou University, Guiyang, Guizhou 550025, China
| | - Pengyao Jin
- Medical College, Guizhou University, Guiyang, Guizhou 550025, China
| | - Yali Zhang
- Medical College, Guizhou University, Guiyang, Guizhou 550025, China
| | - Ming Zhuo
- Medical College, Guizhou University, Guiyang, Guizhou 550025, China
| | - Jubo Wang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
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14
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Masci D, Naro C, Puxeddu M, Urbani A, Sette C, La Regina G, Silvestri R. Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment. Molecules 2023; 28:7513. [PMID: 38005235 PMCID: PMC10672974 DOI: 10.3390/molecules28227513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most heterogeneous and aggressive breast cancer subtypes with a high risk of death on recurrence. To date, TNBC is very difficult to treat due to the lack of an effective targeted therapy. However, recent advances in the molecular characterization of TNBC are encouraging the development of novel drugs and therapeutic combinations for its therapeutic management. In the present review, we will provide an overview of the currently available standard therapies and new emerging therapeutic strategies against TNBC, highlighting the promises that newly developed small molecules, repositioned drugs, and combination therapies have of improving treatment efficacy against these tumors.
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Affiliation(s)
- Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (D.M.); (A.U.)
| | - Chiara Naro
- Department of Neurosciences, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (C.N.); (C.S.)
- GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Michela Puxeddu
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
| | - Andrea Urbani
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (D.M.); (A.U.)
| | - Claudio Sette
- Department of Neurosciences, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (C.N.); (C.S.)
- GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Giuseppe La Regina
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
| | - Romano Silvestri
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
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15
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Zhou AS, Tucker JB, Scribano CM, Lynch AR, Carlsen CL, Pop-Vicas ST, Pattaswamy SM, Burkard ME, Weaver BA. Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles. PLoS Biol 2023; 21:e3002339. [PMID: 37883329 PMCID: PMC10602348 DOI: 10.1371/journal.pbio.3002339] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023] Open
Abstract
Microtubule-targeted agents are commonly used for cancer treatment, though many patients do not benefit. Microtubule-targeted drugs were assumed to elicit anticancer activity via mitotic arrest because they cause cell death following mitotic arrest in cell culture. However, we recently demonstrated that intratumoral paclitaxel concentrations are insufficient to induce mitotic arrest and rather induce chromosomal instability (CIN) via multipolar mitotic spindles. Here, we show in metastatic breast cancer and relevant human cellular models that this mechanism is conserved among clinically useful microtubule poisons. While multipolar divisions typically produce inviable progeny, multipolar spindles can be focused into near-normal bipolar spindles at any stage of mitosis. Using a novel method to quantify the rate of CIN, we demonstrate that cell death positively correlates with net loss of DNA. Spindle focusing decreases CIN and causes resistance to diverse microtubule poisons, which can be counteracted by addition of a drug that increases CIN without affecting spindle polarity. These results demonstrate conserved mechanisms of action and resistance for diverse microtubule-targeted agents. Trial registration: clinicaltrials.gov, NCT03393741.
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Affiliation(s)
- Amber S. Zhou
- Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, United States of America
| | - John B. Tucker
- Cancer Biology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Christina M. Scribano
- Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Andrew R. Lynch
- Cellular and Molecular Pathology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Caleb L. Carlsen
- Cellular and Molecular Biology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Sophia T. Pop-Vicas
- Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Srishrika M. Pattaswamy
- Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Mark E. Burkard
- Department of Medicine, University of Wisconsin, Madison, Wisconsin, United States of America
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Beth A. Weaver
- Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin, United States of America
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, United States of America
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16
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Obata H, Ogawa M, Zalutsky MR. DNA Repair Inhibitors: Potential Targets and Partners for Targeted Radionuclide Therapy. Pharmaceutics 2023; 15:1926. [PMID: 37514113 PMCID: PMC10384049 DOI: 10.3390/pharmaceutics15071926] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
The present review aims to explore the potential targets/partners for future targeted radionuclide therapy (TRT) strategies, wherein cancer cells often are not killed effectively, despite receiving a high average tumor radiation dose. Here, we shall discuss the key factors in the cancer genome, especially those related to DNA damage response/repair and maintenance systems for escaping cell death in cancer cells. To overcome the current limitations of TRT effectiveness due to radiation/drug-tolerant cells and tumor heterogeneity, and to make TRT more effective, we propose that a promising strategy would be to target the DNA maintenance factors that are crucial for cancer survival. Considering their cancer-specific DNA damage response/repair ability and dysregulated transcription/epigenetic system, key factors such as PARP, ATM/ATR, amplified/overexpressed transcription factors, and DNA methyltransferases have the potential to be molecular targets for Auger electron therapy; moreover, their inhibition by non-radioactive molecules could be a partnering component for enhancing the therapeutic response of TRT.
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Affiliation(s)
- Honoka Obata
- Department of Advanced Nuclear Medicine Sciences, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
- Departments of Radiology and Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
- Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan
| | - Mikako Ogawa
- Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan
| | - Michael R Zalutsky
- Departments of Radiology and Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
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17
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Rommasi F. Identification, characterization, and prognosis investigation of pivotal genes shared in different stages of breast cancer. Sci Rep 2023; 13:8447. [PMID: 37231064 DOI: 10.1038/s41598-023-35318-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/16/2023] [Indexed: 05/27/2023] Open
Abstract
One of the leading causes of death (20.1 per 100,000 women per year), breast cancer is the most prevalent cancer in females. Statistically, 95% of breast cancer are categorized as adenocarcinomas, and 55% of all patients may go into invasive phases; however, it can be successfully treated in approximately 70-80% of cases if diagnosed in the nascent stages. The emergence of breast tumor cells which are intensely resistant to conventional therapies, along with the high rate of metastasis occurrence, has highlighted the importance of finding novel strategies and treatments. One of the most advantageous schemes to alleviate this complication is to identify the common differentially expressed genes (DEGs) among primary and metastatic cancerous cells to use resultants for designing new therapeutic agents which are able to target both primary and metastatic breast tumor cells. In this study, the gene expression dataset with accession number GSE55715 was analyzed containing two primary tumor samples, three bone-metastatic samples, and three normal samples to distinguish the up- and down regulated genes in each stage compared to normal cells as control. In the next step, the common upregulated genes between the two experimental groups were detected by Venny online tool. Moreover, gene ontology, functions and pathways, gene-targeting microRNA, and influential metabolites were determined using EnrichR 2021 GO, KEGG pathways miRTarbase 2017, and HMDB 2021, respectively. Furthermore, elicited from STRING protein-protein interaction networks were imported to Cytoscape software to identify the hub genes. Then, identified hub genes were checked to validate the study using oncological databases. The results of the present article disclosed 1263 critical common DEGs (573 upregulated + 690 downregulated), including 35 hub genes that can be broadly used as new targets for cancer treatment and as biomarkers for cancer detection by evaluation of expression level. Besides, this study opens a new horizon to reveal unknown aspects of cancer signaling pathways by providing raw data evoked from in silico experiments. This study's outcomes can also be widely utilized in further lab research since it contains diverse information on common DEGs of varied stages and metastases of breast cancer, their functions, structures, interactions, and associations.
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Affiliation(s)
- Foad Rommasi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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18
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Cosper PF, Hrycyniak LCF, Paracha M, Lee DL, Wan J, Jones K, Bice SA, Nickel K, Mallick S, Taylor AM, Kimple RJ, Lambert PF, Weaver BA. HPV16 E6 induces chromosomal instability due to polar chromosomes caused by E6AP-dependent degradation of the mitotic kinesin CENP-E. Proc Natl Acad Sci U S A 2023; 120:e2216700120. [PMID: 36989302 PMCID: PMC10083562 DOI: 10.1073/pnas.2216700120] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/20/2023] [Indexed: 03/30/2023] Open
Abstract
Chromosome segregation during mitosis is highly regulated to ensure production of genetically identical progeny. Recurrent mitotic errors cause chromosomal instability (CIN), a hallmark of tumors. The E6 and E7 oncoproteins of high-risk human papillomavirus (HPV), which causes cervical, anal, and head and neck cancers (HNC), cause mitotic defects consistent with CIN in models of anogenital cancers, but this has not been studied in the context of HNC. Here, we show that HPV16 induces a specific type of CIN in patient HNC tumors, patient-derived xenografts, and cell lines, which is due to defects in chromosome congression. These defects are specifically induced by the HPV16 oncogene E6 rather than E7. We show that HPV16 E6 expression causes degradation of the mitotic kinesin CENP-E, whose depletion produces chromosomes that are chronically misaligned near spindle poles (polar chromosomes) and fail to congress. Though the canonical oncogenic role of E6 is the degradation of the tumor suppressor p53, CENP-E degradation and polar chromosomes occur independently of p53. Instead, E6 directs CENP-E degradation in a proteasome-dependent manner via the E6-associated ubiquitin protein ligase E6AP/UBE3A. This study reveals a mechanism by which HPV induces CIN, which may impact HPV-mediated tumor initiation, progression, and therapeutic response.
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Affiliation(s)
- Pippa F. Cosper
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI53705
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI53705
| | - Laura C. F. Hrycyniak
- Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin-Madison, Madison, WI53705
| | - Maha Paracha
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI53705
| | - Denis L. Lee
- Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
| | - Jun Wan
- Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI53705
| | - Kathryn Jones
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI53705
| | - Sophie A. Bice
- University of Wisconsin School of Medicine and Public Health, Madison, WI53705
| | - Kwangok Nickel
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI53705
| | - Samyukta Mallick
- Department of Pathology and Cell Biology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY10032
- Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY10032
| | - Alison M. Taylor
- Department of Pathology and Cell Biology at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY10032
| | - Randall J. Kimple
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI53705
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI53705
| | - Paul F. Lambert
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI53705
- Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
| | - Beth A. Weaver
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI53705
- Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI53705
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19
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Aguiar TKB, Mesquita FP, Neto NAS, Gomes FÍR, Freitas CDT, Carneiro RF, Nagano CS, Alencar LMR, Santos-Oliveira R, Oliveira JTA, Souza PFN. No Chance to Survive: Mo-CBP 3-PepII Synthetic Peptide Acts on Cryptococcus neoformans by Multiple Mechanisms of Action. Antibiotics (Basel) 2023; 12:antibiotics12020378. [PMID: 36830289 PMCID: PMC9952340 DOI: 10.3390/antibiotics12020378] [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: 01/19/2023] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/15/2023] Open
Abstract
Multidrug-resistant Cryptococcus neoformans is an encapsulated yeast causing a high mortality rate in immunocompromised patients. Recently, the synthetic peptide Mo-CBP3-PepII emerged as a potent anticryptococcal molecule with an MIC50 at low concentration. Here, the mechanisms of action of Mo-CBP3-PepII were deeply analyzed to provide new information about how it led C. neoformans cells to death. Light and fluorescence microscopies, analysis of enzymatic activities, and proteomic analysis were employed to understand the effect of Mo-CBP3-PepII on C. neoformans cells. Light and fluorescence microscopies revealed Mo-CBP3-PepII induced the accumulation of anion superoxide and hydrogen peroxide in C. neoformans cells, in addition to a reduction in the activity of superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT) in the cells treated with Mo-CBP3-PepII. In the presence of ascorbic acid (AsA), no reactive oxygen species (ROS) were detected, and Mo-CBP3-PepII lost the inhibitory activity against C. neoformans. However, Mo-CBP3-PepII inhibited the activity of lactate dehydrogenase (LDH) ergosterol biosynthesis and induced the decoupling of cytochrome c (Cyt c) from the mitochondrial membrane. Proteomic analysis revealed a reduction in the abundance of proteins related to energetic metabolism, DNA and RNA metabolism, pathogenicity, protein metabolism, cytoskeleton, and cell wall organization and division. Our findings indicated that Mo-CBP3-PepII might have multiple mechanisms of action against C. neoformans cells, mitigating the development of resistance and thus being a potent molecule to be employed in the production of new drugs against C. neoformans infections.
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Affiliation(s)
- Tawanny K. B. Aguiar
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, CE, Brazil
| | - Felipe P. Mesquita
- Drug Research and Development Center, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza 60430-275, CE, Brazil
| | - Nilton A. S. Neto
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, CE, Brazil
| | - Francisco Í. R. Gomes
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, CE, Brazil
| | - Cleverson D. T. Freitas
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, CE, Brazil
| | - Rômulo F. Carneiro
- Department of Fisheries Engineering, Federal University of Ceará (UFC), Fortaleza 60451-970, CE, Brazil
| | - Celso S. Nagano
- Department of Fisheries Engineering, Federal University of Ceará (UFC), Fortaleza 60451-970, CE, Brazil
| | - Luciana M. R. Alencar
- Laboratory of Biophysics and Nanosystems, Physics Department, Federal University of Maranhão, São Luís 65080-805, MA, Brazil
| | - Ralph Santos-Oliveira
- Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Rio de Janeiro 21941-906, RJ, Brazil
- Laboratory of Nanoradiopharmacy, Rio de Janeiro State University, Rio de Janeiro 23070-200, RJ, Brazil
| | - Jose T. A. Oliveira
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, CE, Brazil
| | - Pedro F. N. Souza
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, CE, Brazil
- Drug Research and Development Center, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza 60430-275, CE, Brazil
- Correspondence: or
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20
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Ma L, Xuan XJ, Chen XM, Fan MH, Liu J, Huang GZ, Liu Z. Ethoxysanguinarine Induces Apoptosis, Inhibits Metastasis and Sensitizes cells to Docetaxel in Breast Cancer Cells through Inhibition of Hakai. Chem Biodivers 2023; 20:e202200284. [PMID: 36633334 DOI: 10.1002/cbdv.202200284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/13/2023]
Abstract
Ethoxysanguinarine (ESG) is a benzophenanthridine alkaloid extracted from plants of Papaveraceae family, such as Macleaya cordata (Willd) R. Br. The anti-cancer activity of ESG has been rarely reported. In this study, we investigated the anti-breast cancer effect of ESG and its underlying mechanism. MTT assay and flow cytometry analysis showed that ESG inhibited the viability and induced apoptosis in MCF7 and MDA-MB-231 human breast cancer cells. Western blot revealed that ESG triggered intrinsic and extrinsic apoptotic pathways, as evidenced by the activation of caspase-8, caspase-9 and caspase-3. ESG attenuated breast cancer cell migration and invasion through Hakai/E-cadherin/N-cadherin. Moreover, Hakai knockdown sensitized ESG-triggered viability and motility inhibition, suggesting that Hakai mediated the anti-breast cancer effect of ESG. In addition, ESG potentiated the anti-cancer activity of docetaxel (DTX) in breast cancer cells. Overall, our findings demonstrate that ESG exhibits outstanding pro-apoptosis and anti-metastasis effects on breast cancer via a mechanism related to Hakai-related signaling pathway.
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Affiliation(s)
- Liang Ma
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Xiao-Jing Xuan
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Xue-Ming Chen
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Ming-Hui Fan
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Jian Liu
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Guo-Zheng Huang
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Zi Liu
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
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21
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Ashraf N, Asari A, Yousaf N, Ahmad M, Ahmed M, Faisal A, Saleem M, Muddassar M. Combined 3D-QSAR, molecular docking and dynamics simulations studies to model and design TTK inhibitors. Front Chem 2022; 10:1003816. [PMID: 36405310 PMCID: PMC9666879 DOI: 10.3389/fchem.2022.1003816] [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: 07/26/2022] [Accepted: 10/13/2022] [Indexed: 09/06/2023] Open
Abstract
Tyrosine threonine kinase (TTK) is the key component of the spindle assembly checkpoint (SAC) that ensures correct attachment of chromosomes to the mitotic spindle and thereby their precise segregation into daughter cells by phosphorylating specific substrate proteins. The overexpression of TTK has been associated with various human malignancies, including breast, colorectal and thyroid carcinomas. TTK has been validated as a target for drug development, and several TTK inhibitors have been discovered. In this study, ligand and structure-based alignment as well as various partial charge models were used to perform 3D-QSAR modelling on 1H-Pyrrolo[3,2-c] pyridine core containing reported inhibitors of TTK protein using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches to design better active compounds. Different statistical methods i.e., correlation coefficient of non-cross validation (r2), correlation coefficient of leave-one-out cross-validation (q2), Fisher's test (F) and bootstrapping were used to validate the developed models. Out of several charge models and alignment-based approaches, Merck Molecular Force Field (MMFF94) charges using structure-based alignment yielded highly predictive CoMFA (q2 = 0.583, Predr2 = 0.751) and CoMSIA (q2 = 0.690, Predr2 = 0.767) models. The models exhibited that electrostatic, steric, HBA, HBD, and hydrophobic fields play a key role in structure activity relationship of these compounds. Using the contour maps information of the best predictive model, new compounds were designed and docked at the TTK active site to predict their plausible binding modes. The structural stability of the TTK complexes with new compounds was confirmed using MD simulations. The simulation studies revealed that all compounds formed stable complexes. Similarly, MM/PBSA method based free energy calculations showed that these compounds bind with reasonably good affinity to the TTK protein. Overall molecular modelling results suggest that newly designed compounds can act as lead compounds for the optimization of TTK inhibitors.
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Affiliation(s)
- Noureen Ashraf
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Asnuzilawati Asari
- Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, Kuala Nerus, Terengganu, Malaysia
| | - Numan Yousaf
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Matloob Ahmad
- Department of Chemistry, Government College University, Faisalabad, Pakistan
| | - Mahmood Ahmed
- Department of Chemistry, Division of Science and Technology, University of Education, Lahore, Pakistan
| | - Amir Faisal
- Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan
| | - Muhammad Saleem
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Muhammad Muddassar
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
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22
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Yu J, Gao G, Wei X, Wang Y. TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma. BMC Cancer 2022; 22:786. [PMID: 35850753 PMCID: PMC9290216 DOI: 10.1186/s12885-022-09899-1] [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: 02/15/2022] [Accepted: 07/13/2022] [Indexed: 11/10/2022] Open
Abstract
Background Temozolomide (TMZ) resistance remains the main therapy challenge in patients with glioblastoma multiforme (GBM). TTK Protein Kinase (TTK) contributes to the radioresistance and chemoresistance in many malignancies. However, the role of TTK in the TMZ resistance of GBM cells remains unknown. Methods The expression of TTK was measured by western blot. The proliferation of GBM cells was assessed through MTT assay and clonogenic assay. Cell apoptosis was evaluated using western blot. LC3B puncta were detected using immunohistochemistry staining. The mouse xenograft model was used to investigate the role of TTK in vivo. Results Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model. Conclusions We demonstrated that TTK promotes the TMZ resistance of GBM cells by inducing autophagy in vitro and in vivo. The use of a TTK inhibitor in combination with TMZ might help to overcome TMZ resistance and improve therapy efficiency in GBM. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09899-1.
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Affiliation(s)
- Jian Yu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, Anhui, China
| | - Ge Gao
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, Anhui, China
| | - Xiangpin Wei
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, Anhui, China
| | - Yang Wang
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, Anhui, China.
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23
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Zhu L, Miao Y, Xi F, Jiang P, Xiao L, Jin X, Fang M. Identification of Potential Biomarkers for Pan-Cancer Diagnosis and Prognosis Through the Integration of Large-Scale Transcriptomic Data. Front Pharmacol 2022; 13:870660. [PMID: 35677427 PMCID: PMC9169228 DOI: 10.3389/fphar.2022.870660] [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: 02/10/2022] [Accepted: 03/24/2022] [Indexed: 12/02/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, bringing a significant burden to human health and society. Accurate cancer diagnosis and biomarkers that can be used as robust therapeutic targets are of great importance as they facilitate early and effective therapies. Shared etiology among cancers suggests the existence of pan-cancer biomarkers, performance of which could benefit from the large sample size and the heterogeneity of the studied patients. In this study, we conducted a systematic RNA-seq study of 9,213 tumors and 723 para-cancerous tissue samples of 28 solid tumors from the Cancer Genome Atlas (TCGA) database, and 7,008 normal tissue samples from the Genotype-Tissue Expression (GTEx) database. By differential gene expression analysis, we identified 214 up-regulated and 186 downregulated differentially expressed genes (DEGs) in more than 80% of the studied tumors, respectively, and obtained 20 highly linked up- and downregulated hub genes from them. These markers have rarely been reported in multiple tumors simultaneously. We further constructed pan-cancer diagnostic models to classify tumors and para-cancerous tissues using 10 up-regulated hub genes with an AUC of 0.894. Survival analysis revealed that these hub genes were significantly associated with the overall survival of cancer patients. In addition, drug sensitivity predictions for these hub genes in a variety of tumors obtained several broad-spectrum anti-cancer drugs targeting pan-cancer. Furthermore, we predicted immunotherapy sensitivity for cancers based on tumor mutational burden (TMB) and the expression of immune checkpoint genes (ICGs), providing a theoretical basis for the treatment of tumors. In summary, we identified a set of biomarkers that were differentially expressed in multiple types of cancers, and these biomarkers can be potentially used for diagnosis and used as therapeutic targets.
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Affiliation(s)
- Lin Zhu
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,BGI-Shenzhen, Shenzhen, China
| | - Yu Miao
- BGI-Shenzhen, Shenzhen, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Feng Xi
- BGI-Shenzhen, Shenzhen, China
| | | | - Liang Xiao
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,BGI-Shenzhen, Shenzhen, China
| | - Xin Jin
- BGI-Shenzhen, Shenzhen, China
| | - Mingyan Fang
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,BGI-Shenzhen, Shenzhen, China
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24
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M Serafim RA, da Silva Santiago A, Schwalm MP, Hu Z, Dos Reis CV, Takarada JE, Mezzomo P, Massirer KB, Kudolo M, Gerstenecker S, Chaikuad A, Zender L, Knapp S, Laufer S, Couñago RM, Gehringer M. Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor. J Med Chem 2022; 65:3173-3192. [PMID: 35167750 DOI: 10.1021/acs.jmedchem.1c01165] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.
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Affiliation(s)
- Ricardo A M Serafim
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.,Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.,Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil
| | - André da Silva Santiago
- Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.,Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil
| | - Martin P Schwalm
- Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.,Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany
| | - Zexi Hu
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany
| | - Caio V Dos Reis
- Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.,Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil
| | - Jessica E Takarada
- Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.,Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil
| | - Priscila Mezzomo
- Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.,Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil
| | - Katlin B Massirer
- Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.,Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil
| | - Mark Kudolo
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
| | - Stefan Gerstenecker
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
| | - Apirat Chaikuad
- Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.,Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany
| | - Lars Zender
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany.,German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 72076 Tübingen, Germany
| | - Stefan Knapp
- Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.,Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.,Frankfurt Cancer Institute (FCI) and German Translational Cancer Network (DKTK) Site Frankfurt/Mainz, 60596 Frankfurt am Main, Germany
| | - Stefan Laufer
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany.,Tübingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, 72076 Tübingen, Germany
| | - Rafael M Couñago
- Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.,Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil
| | - Matthias Gehringer
- Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.,Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany
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25
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Cosper PF, Copeland SE, Tucker JB, Weaver BA. Chromosome Missegregation as a Modulator of Radiation Sensitivity. Semin Radiat Oncol 2022; 32:54-63. [PMID: 34861996 PMCID: PMC8883596 DOI: 10.1016/j.semradonc.2021.09.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Chromosome missegregation over the course of multiple cell divisions, termed chromosomal instability (CIN), is a hallmark of cancer. Multiple causes of CIN have been identified, including defects in the mitotic checkpoint, altered kinetochore-microtubule dynamics, centrosome amplification, and ionizing radiation. Here we review the types, mechanisms, and cellular implications of CIN. We discuss the evidence that CIN can promote tumors, suppress them, or do neither, depending on the rates of chromosome missegregration and the cellular context. Very high rates of chromosome missegregation lead to cell death due to loss of essential chromosomes; thus elevating CIN above a tolerable threshold provides a mechanistic opportunity to promote cancer cell death. Lethal rates of CIN can be achieved by a single insult or through a combination of insults. Because ionizing radiation induces CIN, additional therapies that increase CIN may serve as useful modulators of radiation sensitivity. Ultimately, quantifying the intrinsic CIN in a tumor and modulating this level pharmacologically as well as with radiation may allow for a more rational, personalized radiation therapy prescription, thereby decreasing side effects and increasing local control.
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Affiliation(s)
- Pippa F. Cosper
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA,University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Sarah E. Copeland
- Molecular & Cellular Pharmacology Graduate Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - John B. Tucker
- Cancer Biology Graduate Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Beth A. Weaver
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA,Department of Cellular and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA,Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA,Corresponding author: Beth A. Weaver, University of Wisconsin-Madison, 1111 Highland Ave, 6109 WIMR Tower 1, Madison, WI 53705-2275, Phone: 608-263-5309, Fax: 608-265-6905,
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26
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Qi G, Ma H, Li Y, Peng J, Chen J, Kong B. TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway. Cell Death Dis 2021; 12:1135. [PMID: 34876569 PMCID: PMC8651821 DOI: 10.1038/s41419-021-04429-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 11/09/2021] [Accepted: 11/22/2021] [Indexed: 12/25/2022]
Abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.
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Affiliation(s)
- Gonghua Qi
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China
| | - Hanlin Ma
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China
| | - Yingwei Li
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China
| | - Jiali Peng
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China
| | - Jingying Chen
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China.
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China.
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27
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Yao ZP, Zhu H, Shen F, Gong D. Hsp90 regulates the tumorigenic function of tyrosine protein kinase in osteosarcoma. Clin Exp Pharmacol Physiol 2021; 49:380-390. [PMID: 34767669 DOI: 10.1111/1440-1681.13613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/30/2021] [Accepted: 11/08/2021] [Indexed: 01/04/2023]
Abstract
Despite recent advances in diagnosis and treatment, osteosarcoma remains as the most common bone cancer in children and is associated with poor prognosis. Growing evidence has supported dysregulation of threonine and tyrosine protein kinase (TTK) expression as a hallmark of multiple cancers, however, its function in osteosarcoma remains to be elucidated. In the present study, we found that TTK was frequently overexpressed in osteosarcoma and associated with increased tumour growth and progression. Moreover, using both in vitro and in vivo assays, we provided evidence that TTK level was regulated by a molecular chaperone, heat shock protein 90 (Hsp90). Hsp90 directly interacted with TTK and prevents proteasome-dependent TTK degradation, leading to the accumulation of TTK in osteosarcoma cells. Elevated TTK promoted cancer cell proliferation and survival by activating cell-cycle progression and inhibiting apoptosis. Consistently, depletion of TTK by Hsp90 inhibition induced cell-cycle arrest, generated aneuploidy and eventually resulted in apoptotic cancer cell death. Together, our study revealed an important Hsp90-TTK regulatory axis in osteosarcoma cells to promote cancer cell growth and survival. These findings expand our knowledge on osteosarcoma pathogenesis and offer novel therapeutic options for clinical practice.
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Affiliation(s)
- Zhao-Peng Yao
- Department of Orthopaedics, The First Hospital of Nanchang, Nanchang, China
| | - Hui Zhu
- Department of Breast Cancer Surgery, Jiangxi Provincial Cancer Hospital, Nanchang, China
| | - Feng Shen
- Department of Orthopaedics, The First Hospital of Nanchang, Nanchang, China
| | - Dan Gong
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
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28
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Qiao EQ, Yang HJ, Yu XF, Gong LJ, Zhang XP, Chen DB. Curcuma zedoaria petroleum ether extract reverses the resistance of triple-negative breast cancer to docetaxel via pregnane X receptor. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1389. [PMID: 34733941 PMCID: PMC8506551 DOI: 10.21037/atm-21-4199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/02/2021] [Indexed: 11/21/2022]
Abstract
Background Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and poor prognosis. Docetaxel is the common chemotherapeutic drug used in the treatment of TNBC. However, resistance to docetaxel has limited the effectiveness of TNBC treatment. Petroleum ether extracts of Curcuma zedoaria (PECZ) can inhibit the proliferation of MDA-MB-231 cells. However, the effect of PECZ on docetaxel resistance is not clear. Methods A docetaxel-resistant MDA-MB-231 (MDA-MB-231/docetaxel) cell line was established, and Cell Counting Kit-8 (CCK-8), quantitative real-time PCR (qRT-PCR), and western blotting assays were used to evaluate the effect of docetaxel resistance in MDA-MB-231 cells. Next, CCK-8 was also performed to detect the effect of docetaxel or the combination treatment of docetaxel and PECZ on the proliferation of MDA-MB-231/docetaxel cells. Thereafter, MDA-MB-231/docetaxel cells were subcutaneously injected into nude mice to induce a TNBC xenograft model, and the mice were divided into a model group, docetaxel group, PECZ group, and combination of docetaxel and PECZ group. Subsequently, hematoxylin and eosin (HE) staining, immunohistochemical, qRT-PCR, and western blotting were used to estimate the effect of pre-treatment with PECZ on docetaxel tolerance reversal. Results PECZ significantly inhibited the expression of pregnane X receptor (PXR), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and cytochrome P-450 (CYP3A4) in MDA-MB-231/docetaxel cells. Only higher concentrations of docetaxel could inhibit the viability of MDA-MB-231/docetaxel cells. When pre-treated with PECZ, lower concentrations of docetaxel could significantly inhibit cell viability. Meanwhile, combination treatment also reduced the tumor volume, ameliorated the pathological change of tumor tissues, and down-regulated the expressions of PXR, MDR1, BCRP, and CYP3A4 (according to HE staining, immunohistochemical, qRT-PCR and western blotting results in vivo). Conclusions Our research showed that PECZ reversed docetaxel resistance in TNBC by PXR both in vitro and in vivo, which provides the basis for further investigations into the potential therapeutic impact of docetaxel resistance in TNBC.
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Affiliation(s)
- En-Qi Qiao
- Department of Breast Tumor Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Hong-Jian Yang
- Department of Breast Tumor Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xing-Fei Yu
- Department of Breast Tumor Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Li-Jie Gong
- Department of Breast Tumor Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xi-Ping Zhang
- Department of Breast Tumor Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Dao-Bao Chen
- Department of Breast Tumor Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
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Liu Y, Zhu K, Guan X, Xie S, Wang Y, Tong Y, Guo L, Zheng H, Lu R. TTK is a potential therapeutic target for cisplatin-resistant ovarian cancer. J Ovarian Res 2021; 14:128. [PMID: 34598710 PMCID: PMC8487155 DOI: 10.1186/s13048-021-00884-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 09/19/2021] [Indexed: 12/17/2022] Open
Abstract
Background Drug resistance and recurrence are main contributors to the poor prognosis of ovarian cancer. Cisplatin is a platinum compound which is widely used in the treatment of various solid tumors including ovarian cancer. Up to now, the mechanism of cisplatin resistance in ovarian cancer is unclear. Threonine and tyrosine kinase (TTK), an integral part of the spindle assembly checkpoint, may be a potential new target associated with chemotherapy sensitivity. Results TTK was up-regulated in the cisplatin-resistant ovarian cancer cell line. Down-regulation of TTK could recover the sensitivity of cisplatin-resistant ovarian cancer cells to cisplatin treatment. Mechanistically, the PI3K/AKT signaling pathway was activated in cisplatin-resistant cells, and this pathway would be affected by TTK expression. Furthermore, TTK was highly expressed in the tissues of ovarian cancer patients, especially those acquired resistance to cisplatin. Conclusions Our study revealed that TTK may be a promising therapeutic target for cisplatin-resistant ovarian cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-021-00884-z.
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Affiliation(s)
- Yixuan Liu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Keyu Zhu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaolin Guan
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China
| | - Yanchun Wang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China
| | - Ying Tong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China.
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong'An Road, Xuhui District, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Gene Expression Analysis Reveals Key Genes and Signalings Associated with the Prognosis of Prostate Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:9946015. [PMID: 34497666 PMCID: PMC8419495 DOI: 10.1155/2021/9946015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/07/2021] [Indexed: 12/24/2022]
Abstract
It is urgent to identify novel biomarkers for prostate cancer (PCa) prognosis and to understand the mechanisms regulating the tumorigenesis for PCa treatment. In this study, GSE17951 and TCGA were used to identify the differentially expressed genes (DEGs). Our study demonstrated that 1533 genes with increased expression and 2301 genes with decreased expression in PCa. Bioinformatics analysis data indicated that these up-regulated genes had an association with the modulation of mitotic nuclear division, sister chromatid cohesion, cell division, and cell cycle. Additionally, our results revealed downregulated genes took part in modulating extracellular matrix organization, angiogenesis, signal transduction, and Ras signaling pathway. Hub upregulated and downregulated PPI networks were identified by protein-protein interaction (PPI) network analysis and MCODE analysis. Of note, 12 cell cycle regulators, comprising CCNB1, CCNB2, PLK1, TTK, AURKA, CDC20, BUB1, PTTG1, CDC45, CDC25C, CCNA2, and BUB1B, were demonstrated to function crucially in PCa development. By detecting their expression in PCa cell lines, we confirmed that these cell cycle regulator expressions were heightened in PCa cells. GEPIA databases analysis showed that higher expression of these cell cycle regulators was correlated to shorter disease-free survival (DFS) time in PCa samples. Our findings collectively suggested targeting cell cycle pathways may offer novel prognosis and treatment biomarkers for PCa.
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31
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Su T, Qin XY, Dohmae N, Wei F, Furutani Y, Kojima S, Yu W. Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling. Metabolites 2021; 11:metabo11030167. [PMID: 33803928 PMCID: PMC7998610 DOI: 10.3390/metabo11030167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/27/2021] [Accepted: 03/11/2021] [Indexed: 01/01/2023] Open
Abstract
The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment.
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Affiliation(s)
- Ting Su
- Department of Intensive Care Unit, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China;
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; (Y.F.); (S.K.)
| | - Xian-Yang Qin
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; (Y.F.); (S.K.)
- Correspondence: (X.-Y.Q.); (W.Y.); Tel.: +81-(48)-467-7938 (X.-Y.Q.); +86-(25)-6818-2222 (W.Y.)
| | - Naoshi Dohmae
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan;
| | - Feifei Wei
- Metabolomics Research Group, RIKEN Center for Sustainable Resource Science, Kanagawa, Yokohama 230-0045, Japan;
| | - Yutaka Furutani
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; (Y.F.); (S.K.)
| | - Soichi Kojima
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; (Y.F.); (S.K.)
| | - Wenkui Yu
- Department of Intensive Care Unit, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China;
- Correspondence: (X.-Y.Q.); (W.Y.); Tel.: +81-(48)-467-7938 (X.-Y.Q.); +86-(25)-6818-2222 (W.Y.)
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Liao M, Zhang J, Wang G, Wang L, Liu J, Ouyang L, Liu B. Small-Molecule Drug Discovery in Triple Negative Breast Cancer: Current Situation and Future Directions. J Med Chem 2021; 64:2382-2418. [PMID: 33650861 DOI: 10.1021/acs.jmedchem.0c01180] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but an effective targeted therapy has not been well-established so far. Considering the lack of effective targets, where do we go next in the current TNBC drug development? A promising intervention for TNBC might lie in de novo small-molecule drugs that precisely target different molecular characteristics of TNBC. However, an ideal single-target drug discovery still faces a huge challenge. Alternatively, other new emerging strategies, such as dual-target drug, drug repurposing, and combination strategies, may provide new insight into the improvement of TNBC therapeutics. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in TNBC therapy, including single-target drugs, dual-target drugs, as well as drug repurposing and combination strategies that will together shed new light on the future directions targeting TNBC vulnerabilities with small-molecule drugs for future therapeutic purposes.
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Affiliation(s)
- Minru Liao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jin Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Leiming Wang
- The Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518107, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
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Sakalli-Tecim E, Uyar-Arpaci P, Guray NT. Identification of Potential Therapeutic Genes and Pathways in Phytoestrogen Emodin Treated Breast Cancer Cell Lines via Network Biology Approaches. Nutr Cancer 2021; 74:592-604. [PMID: 33645356 DOI: 10.1080/01635581.2021.1889622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Phytoestrogens have been investigated for their potential anti-tumorigenic effects in various cancers including breast cancer. Emodin being a phytoestrogen shows anti-carcinogenic properties especially in estrogen receptor positive (ER+) breast cancers. The aim of this study is to identify the molecular mechanism and related biological pathways in both (ER+) MCF-7 and (ER-) MDA-MB-231 breast cancer cell lines upon Emodin treatment via microarray analysis in order to find out therapeutic biomarkers. In both cell lines, first differentially expressed genes were identified, then gene ontology and functional pathway enrichment analyses were performed. Genes regulated through multiple pathways were studied together with literature and a gene cluster was determined for each cell line. Further GeneMANIA and STRING databases were used to study the interactions within the related gene clusters. The results showed that, the genes which are related to cell cycle were significantly regulated in both cell lines. Also, Forkhead Box O1-related genes were found to be prominent in MCF-7 cells. In MDA-MB-231 cells, spindle attachment checkpoint mechanism-related genes were regulated, remarkably. As a result, novel gene regulations reported in this study in response to Emodin will give more information about its metabolism and antiproliferative effect, especially in ER + cells.
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Affiliation(s)
- Elif Sakalli-Tecim
- Department of Biotechnology, Middle East Technical University, Ankara, Turkey
| | | | - N Tulin Guray
- Department of Biotechnology, Middle East Technical University, Ankara, Turkey.,Department of Biological Sciences, Middle East Technical University, Ankara, Turkey
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34
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Wang Y, Zhou Z, Chen L, Li Y, Zhou Z, Chu X. Identification of key genes and biological pathways in lung adenocarcinoma via bioinformatics analysis. Mol Cell Biochem 2021; 476:931-939. [PMID: 33130972 DOI: 10.1007/s11010-020-03959-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Lung adenocarcinoma (LUAD) accounts for the majority of cancer-related deaths worldwide. Our study identified key LUAD genes and their potential mechanism via bioinformatics analysis of public datasets. GSE10799, GSE40791, and GSE27262 microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database. The RobustRankAggreg package was used to perform a meta-analysis, and 50 upregulated genes and 87 downregulated genes overlapped in three datasets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Furthermore, protein-protein interaction (PPI) networks of the differentially expressed genes (DEGs) were built by the Search Tool for the Retrieval of Interacting Genes (STRING) and 22 core genes were identified by Molecular Complex Detection (MCODE) and visualized with Cytoscape. Subsequently, these core genes were analyzed by the Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis (GEPIA). The results showed that all 22 genes were significantly associated with reduced survival rates. For GEPIA, the expression of only one gene was not significantly different between LUAD tissues and normal tissues. A KEGG pathway enrichment reanalysis of the 21 genes identified five key genes (CCNB1, BUB1B, CDC20, TTK, and MAD2L1) in the cell cycle pathway. Finally, the Comparative Toxicogenomics Database (CTD) website was used to explore the relationship between these key genes and certain drugs. Based on the bioinformatics analysis, five key genes were identified in LUAD, and drugs closely associated these genes can provide clues for the treatment and prognosis of LUAD.
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Affiliation(s)
- Yuanyuan Wang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Zihao Zhou
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Liang Chen
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Yuzheng Li
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Zengyuan Zhou
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China
| | - Xia Chu
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Hei Longjiang Province, 150081, P. R. China.
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Vasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nat Rev Cancer 2021; 21:89-103. [PMID: 33432169 DOI: 10.1038/s41568-020-00321-1] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
Abstract
Aneuploidy has been recognized as a hallmark of tumorigenesis for more than 100 years, but the connection between chromosomal errors and malignant growth has remained obscure. New evidence emerging from both basic and clinical research has illuminated a complicated relationship: despite its frequency in human tumours, aneuploidy is not a universal driver of cancer development and instead can exert substantial tumour-suppressive effects. The specific consequences of aneuploidy are highly context dependent and are influenced by a cell's genetic and environmental milieu. In this Review, we discuss the diverse facets of cancer biology that are shaped by aneuploidy, including metastasis, drug resistance and immune recognition, and we highlight aneuploidy's distinct roles as both a tumour promoter and an anticancer vulnerability.
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Han TL, Sha H, Ji J, Li YT, Wu DS, Lin H, Hu B, Jiang ZX. Depletion of Survivin suppresses docetaxel-induced apoptosis in HeLa cells by facilitating mitotic slippage. Sci Rep 2021; 11:2283. [PMID: 33504817 PMCID: PMC7840972 DOI: 10.1038/s41598-021-81563-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 01/03/2021] [Indexed: 12/11/2022] Open
Abstract
The anticancer effects of taxanes are attributed to the induction of mitotic arrest through activation of the spindle assembly checkpoint. Cell death following extended mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression is associated with chemoresistance, and its targeting leads to drug sensitization. However, Survivin also acts specifically in the spindle assembly checkpoint response to taxanes. Hence, the failure of Survivin-depleted cells to arrest in mitosis may lead to taxane resistance. Here we show that Survivin depletion protects HeLa cells against docetaxel-induced apoptosis by facilitating mitotic slippage. However, Survivin depletion does not promote clonogenic survival of tumor cells but increases the level of cellular senescence induced by docetaxel. Moreover, lentiviral overexpression of Survivin does not provide protection against docetaxel or cisplatin treatment, in contrast to the anti-apoptotic Bcl-xL or Bcl-2. Our findings suggest that targeting Survivin may influence the cell response to docetaxel by driving the cells through aberrant mitotic progression, rather than directly sensitizing cells to apoptosis.
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Affiliation(s)
- Teng-Long Han
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China.
| | - Hang Sha
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China
| | - Jun Ji
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China
| | - Yun-Tian Li
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China
| | - Deng-Shan Wu
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China
| | - Hu Lin
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China
| | - Bin Hu
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China
| | - Zhi-Xin Jiang
- The 305 Hospital of the People's Liberation Army, Beijing, 100017, China.
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Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice. Sci Rep 2021; 11:68. [PMID: 33420244 PMCID: PMC7794249 DOI: 10.1038/s41598-020-80169-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 12/15/2020] [Indexed: 11/08/2022] Open
Abstract
Chromosomal instability (CIN) is a hallmark of cancer, leading to aneuploid cells. To study the role that CIN plays in tumor evolution, several mouse models have been engineered over the last 2 decades. These models have unequivocally shown that systemic high-grade CIN is embryonic lethal. We and others have previously shown that embryonic lethality can be circumvented by provoking CIN in a tissue-specific fashion. In this study, we provoke systemic high-grade CIN in adult mice as an alternative to circumvent embryonic lethality. For this, we disrupt the spindle assembly checkpoint (SAC) by alleviating Mad2 or truncating Mps1, both essential genes for SAC functioning, with or without p53 inactivation. We find that disruption of the SAC leads to rapid villous atrophy, atypia and apoptosis of the epithelia of the jejunum and ileum, substantial weight loss, and death within 2-3 weeks after the start of the CIN insult. Despite this severe intestinal phenotype, most other tissues are unaffected, except for minor abnormalities in spleen, presumably due to the lower proliferation rate in these tissues. We conclude that high-grade CIN in vivo in adult mice is most toxic to the high cell turnover intestinal epithelia.
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Funk LC, Wan J, Ryan SD, Kaur C, Sullivan R, Roopra A, Weaver BA. p53 Is Not Required for High CIN to Induce Tumor Suppression. Mol Cancer Res 2021; 19:112-123. [PMID: 32948674 PMCID: PMC7810023 DOI: 10.1158/1541-7786.mcr-20-0488] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/14/2020] [Accepted: 09/13/2020] [Indexed: 11/16/2022]
Abstract
Chromosomal instability (CIN) is a hallmark of cancer. While low levels of CIN can be tumor promoting, high levels of CIN cause cell death and tumor suppression. The widely used chemotherapeutic, paclitaxel (Taxol), exerts its anticancer effects by increasing CIN above a maximally tolerated threshold. One significant outstanding question is whether the p53 tumor suppressor is required for the cell death and tumor suppression caused by high CIN. Both p53 loss and reduction of the mitotic kinesin, centromere-associated protein-E, cause low CIN. Combining both genetic insults in the same cell leads to high CIN. Here, we test whether high CIN causes cell death and tumor suppression even in the absence p53. Despite a surprising sex-specific difference in tumor spectrum and latency in p53 heterozygous animals, these studies demonstrate that p53 is not required for high CIN to induce tumor suppression. Pharmacologic induction of high CIN results in equivalent levels of cell death due to loss of essential chromosomes in p53+/+ and p53-/- cells, further demonstrating that high CIN elicits cell death independently of p53 function. IMPLICATIONS: These results provide support for the efficacy of anticancer therapies that induce high CIN, even in tumors that lack functional p53.
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Affiliation(s)
- Laura C Funk
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Jun Wan
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Sean D Ryan
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Charanjeet Kaur
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Ruth Sullivan
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin
| | - Avtar Roopra
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin
| | - Beth A Weaver
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin
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Maan M, Agrawal NJ, Padmanabhan J, Leitzinger CC, Rivera-Rivera Y, Saavedra HI, Chellappan SP. Tank Binding Kinase 1 modulates spindle assembly checkpoint components to regulate mitosis in breast and lung cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1868:118929. [PMID: 33310066 DOI: 10.1016/j.bbamcr.2020.118929] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/17/2020] [Accepted: 12/07/2020] [Indexed: 11/25/2022]
Abstract
Error-free progression through mitosis is critical for proper cell division and accurate distribution of the genetic material. The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase regulates the progression from metaphase to anaphase and its activation is controlled by the cofactors Cdc20 and Cdh1. Additionally, genome stability is maintained by the spindle assembly checkpoint (SAC), which monitors proper attachment of chromosomes to spindle microtubules prior to cell division. We had shown a role for Tank Binding Kinase 1 (TBK1) in microtubule dynamics and mitosis and here we describe a novel role of TBK1 in regulating SAC in breast and lung cancer cells. TBK1 interacts with and phosphorylates Cdc20 and Cdh1 and depletion of TBK1 elevates SAC components. TBK1 inhibition increases the association of Cdc20 with APC/C and BubR1 indicating inactivation of APC/C; similarly, interaction of Cdh1 with APC/C is also enhanced. TBK1 and TTK inhibition reduces cell viability and enhances centrosome amplification and micronucleation. These results indicate that alterations in TBK1 will impede mitotic progression and combining TBK1 inhibitors with other regulators of mitosis might be effective in eliminating cancer cells.
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Affiliation(s)
- Meenu Maan
- Department of Tumor Biology, H, Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, United States of America
| | - Neha Jaiswal Agrawal
- Department of Tumor Biology, H, Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, United States of America
| | - Jaya Padmanabhan
- Department of Tumor Biology, H, Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, United States of America
| | - Christelle Colin Leitzinger
- Department of Tumor Biology, H, Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, United States of America
| | - Yainyrette Rivera-Rivera
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, Ponce Health Sciences University/Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Harold I Saavedra
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, Ponce Health Sciences University/Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Srikumar P Chellappan
- Department of Tumor Biology, H, Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, United States of America.
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TTK, CDC25A, and ESPL1 as Prognostic Biomarkers for Endometrial Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4625123. [PMID: 33282948 PMCID: PMC7685798 DOI: 10.1155/2020/4625123] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/19/2020] [Accepted: 10/30/2020] [Indexed: 12/24/2022]
Abstract
Objective Endometrial cancer (EC) is one of the most common malignant gynaecological tumours worldwide. This study was aimed at identifying EC prognostic genes and investigating the molecular mechanisms of these genes in EC. Methods Two mRNA datasets of EC were downloaded from the Gene Expression Omnibus (GEO). The GEO2R tool and Draw Venn Diagram were used to identify differentially expressed genes (DEGs) between normal endometrial tissues and EC tissues. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Next, the protein-protein interactions (PPIs) of these DEGs were determined by the Search Tool for the Retrieval of Interacting Genes (STRING) tool and Cytoscape with Molecular Complex Detection (MCODE). Furthermore, Kaplan-Meier survival analysis was performed by UALCAN to verify genes associated with significantly poor prognosis. Next, Gene Expression Profiling Interactive Analysis (GEPIA) was used to verify the expression levels of these selected genes. Additionally, a reanalysis of the KEGG pathways was performed to understand the potential biological functions of selected genes. Finally, the associations between these genes and clinical features were analysed based on TCGA cancer genomic datasets for EC. Results In EC tissues, compared with normal endometrial tissues, 147 of 249 DEGs were upregulated and 102 were downregulated. A total of 64 upregulated genes were assembled into a PPI network. Next, 14 genes were found to be both associated with significantly poor prognosis and highly expressed in EC tissues. Reanalysis of the KEGG pathways found that three of these genes were enriched in the cell cycle pathway. TTK, CDC25A, and ESPL1 showed higher expression in cancers with late stage and higher tumour grade. Conclusion In summary, through integrated bioinformatics approaches, we found three significant prognostic genes of EC, which might be potential therapeutic targets for EC patients.
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Huang C, Hu CG, Ning ZK, Huang J, Zhu ZM. Identification of key genes controlling cancer stem cell characteristics in gastric cancer. World J Gastrointest Surg 2020; 12:442-459. [PMID: 33304447 PMCID: PMC7701879 DOI: 10.4240/wjgs.v12.i11.442] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/13/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Self-renewal of gastric cancer stem cells (GCSCs) is considered to be the underlying cause of the metastasis, drug resistance, and recurrence of gastric cancer (GC).
AIM To characterize the expression of stem cell-related genes in GC.
METHODS RNA sequencing results and clinical data for gastric adenoma and adenocarcinoma samples were obtained from The Cancer Genome Atlas database, and the results of the GC mRNA expression-based stemness index (mRNAsi) were analyzed. Weighted gene coexpression network analysis was then used to find modules of interest and their key genes. Survival analysis of key genes was performed using the online tool Kaplan-Meier Plotter, and the online database Oncomine was used to assess the expression of key genes in GC.
RESULTS mRNAsi was significantly upregulated in GC tissues compared to normal gastric tissues (P < 0.0001). A total of 16 modules were obtained from the gene coexpression network; the brown module was most positively correlated with mRNAsi. Sixteen key genes (BUB1, BUB1B, NCAPH, KIF14, RACGAP1, RAD54L, TPX2, KIF15, KIF18B, CENPF, TTK, KIF4A, SGOL2, PLK4, XRCC2, and C1orf112) were identified in the brown module. The functional and pathway enrichment analyses showed that the key genes were significantly enriched in the spindle cellular component, the sister chromatid segregation biological process, the motor activity molecular function, and the cell cycle and homologous recombination pathways. Survival analysis and Oncomine analysis revealed that the prognosis of patients with GC and the expression of three genes (RAD54L, TPX2, and XRCC2) were consistently related.
CONCLUSION Sixteen key genes are primarily associated with stem cell self-renewal and cell proliferation characteristics. RAD54L, TPX2, and XRCC2 are the most likely therapeutic targets for inhibiting the stemness characteristics of GC cells.
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Affiliation(s)
- Chao Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Ce-Gui Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Zhi-Kun Ning
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jun Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Zheng-Ming Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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Singh A, Denu RA, Wolfe SK, Sperger JM, Schehr J, Witkowsky T, Esbona K, Chappell RJ, Weaver BA, Burkard ME, Lang JM. Centrosome amplification is a frequent event in circulating tumor cells from subjects with metastatic breast cancer. Mol Oncol 2020; 14:1898-1909. [PMID: 32255253 PMCID: PMC7400789 DOI: 10.1002/1878-0261.12687] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 03/03/2020] [Accepted: 03/07/2020] [Indexed: 01/05/2023] Open
Abstract
Centrosome amplification (CA) is a common phenomenon in cancer, promotes genomic stability and cancer evolution, and has been reported to promote metastasis. CA promotes a stochastic gain/loss of chromosomes during cell division, known as chromosomal instability (CIN). However, it is unclear whether CA is present in circulating tumor cells (CTCs), the seeds for metastasis. Here, we surveyed CA in CTCs from human subjects with metastatic breast cancer. CTCs were captured by CD45 exclusion and selection of EpCAM‐positive cells using an exclusion‐based sample preparation technology platform known as VERSA (versatile exclusion‐based rare sample analysis). Centriole amplification (centrin foci> 4) is the definitive assay for CA. However, determination of centrin foci is technically challenging and incompatible with automated analysis. To test if the more technically accessible centrosome marker pericentrin could serve as a surrogate for centriole amplification in CTCs, cells were stained with pericentrin and centrin antibodies to evaluate CA. This assay was first validated using breast cancer cell lines and a nontransformed epithelial cell line model of inducible CA, then translated to CTCs. Pericentrin area and pericentrin area x intensity correlate well with centrin foci, validating pericentrin as a surrogate marker of CA. CA is found in CTCs from 75% of subjects, with variability in the percentage and extent of CA in individual circulating cells in a given subject, similar to the variability previously seen in primary tumors and cell lines. In summary, we created, validated, and implemented a novel method to assess CA in CTCs from subjects with metastatic breast cancer. Such an assay will be useful for longitudinal monitoring of CA in cancer patients and in prospective clinical trials for assessing the impact of CA on response to therapy.
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Affiliation(s)
- Ashok Singh
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA
| | - Ryan A Denu
- Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison, WI, USA
| | - Serena K Wolfe
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA
| | - Jamie M Sperger
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA
| | - Jennifer Schehr
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA
| | - Tessa Witkowsky
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA
| | - Karla Esbona
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA
| | - Richard J Chappell
- Departments of Statistics and of Biostatistics & Medical Informatics, University of Wisconsin-Madison, WI, USA
| | - Beth A Weaver
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA.,Department of Cell and Regenerative Biology and Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, WI, USA
| | - Mark E Burkard
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA.,Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison, WI, USA
| | - Joshua M Lang
- Carbone Cancer Center, University of Wisconsin-Madison, WI, USA.,Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison, WI, USA
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Integrated Bioinformatics Analysis of the Clinical Value and Biological Function of ATAD2 in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8657468. [PMID: 32462022 PMCID: PMC7225861 DOI: 10.1155/2020/8657468] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 02/14/2020] [Accepted: 03/06/2020] [Indexed: 02/07/2023]
Abstract
ATPase family AAA domain-containing protein 2 (ATAD2), a chromatin regulator and an oncogenic transcription cofactor, is frequently overexpressed in many cancers, particularly in hepatocellular carcinoma (HCC). By integrating open-access online mRNA datasets and our institutional tissue data on HCC, the clinical role and functions of ATAD2 were analyzed by bioinformatic algorithms. We systematically examined ATAD2 expression in HCC based on a large sample population, integrating data from our institution and the GEO, Oncomine, and TCGA datasets. Aberrant ATAD2 expression related to pathways was identified by bioinformatic algorithms. The effects of ATAD2 downregulation on the cycle cell were also determined. A pooled analysis from 28 datasets indicated that ATAD2 overexpression was found in HCC (SMD = 8.88, 95% CI: 5.96–11.81, P < 0.001) and was correlated with poor survival. Subgroup analysis of Asian patients with a serum alpha-fetoprotein (AFP) concentration < 200 ng/ml in stage I + II showed that the ATAD2-high group had a more unfavorable overall survival (OS) rate than the ATAD2-low group. The receiver operating characteristic curve indicated that the efficiency of ATAD2 for HCC diagnosis was considerable (area under the curve = 0.89, 95% CI: 0.86–0.91). Functional analysis based on bioinformatic algorithms demonstrated that ATAD2 participates in cell division, mitotic nuclear division, DNA replication, repair, and cell cycle processes. ATAD2 knockout in HCC cells downregulated cyclin C and cyclin D1 protein levels and resulted in G1/S phase arrest in vitro. The kinesin family member C1 (KIFC1), shugoshin 1 (SGO1), GINS complex subunit 1 (GINS1), and TPX2 microtubule nucleation factor (TPX2) genes were closely related to ATAD2 upregulation. ATAD2 may interact with TTK protein kinase (TTK) to accelerate HCC carcinogenesis. ATAD2 plays a vital role in HCC carcinogenesis by disturbing the interaction between chromatin proteins and DNA. Targeting ATAD2 represents a promising method for the development of therapeutic treatments for cancer.
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Gisler S, Maia ARR, Chandrasekaran G, Kopparam J, van Lohuizen M. A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition. PLoS One 2020; 15:e0227592. [PMID: 32343689 PMCID: PMC7188281 DOI: 10.1371/journal.pone.0227592] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/24/2020] [Indexed: 02/02/2023] Open
Abstract
BMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 or BMI1 knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derived NUMA1 knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role of NUMA1 in this process.
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Affiliation(s)
- Santiago Gisler
- Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ana Rita R. Maia
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Gayathri Chandrasekaran
- Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jawahar Kopparam
- Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Maarten van Lohuizen
- Division of Molecular Genetics, Oncode and The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Evaluation of ASPM and TEF Gene Expressions as Potential Biomarkers for Bladder Cancer. Biochem Genet 2020; 58:490-507. [PMID: 32274607 DOI: 10.1007/s10528-020-09962-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 04/02/2020] [Indexed: 02/04/2023]
Abstract
Bladder cancer is one of the most predominant tumors of the genitourinary tract. In addition to pathological findings, the molecular modifications that might affect tumorigenesis and tumor outcome should be considered when treating bladder cancer. Accordingly, we aimed to investigate the expression levels of both the ASPM and TEF genes in bladder cancer tissues and their value in disease prognosis. The expression levels of the ASPM and TEF genes were analyzed by quantitative real-time PCR (qRT-PCR) in 90 bladder cancer tissue specimens and 90 specimens of normal urinary bladder tissue taken away from the tumor site. The upregulation of ASPM expression and the downregulation of TEF expression were observed in bladder cancer tissues compared to adjacent normal tissues, and these levels were correlated with high-grade tumors, advanced stage disease and the presence of metastasis. Both genes had the ability to predict metastatic association with sensitivity (84.62%) and specificity (68.42%; *P < 0.001) for the ASPM gene and for the TEF gene with sensitivity (80.77%) and specificity (78.95%; *P < 0.001). Additionally, Kaplan-Meier survival analysis indicated that elevated ASPM expression levels and reduced TEF expression levels significantly correlated with decreased overall survival and progression-free survival. The current analysis concludes that ASPM and TEF expressions might be used as potential biomarkers in bladder cancer patients.
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Jiang W, Wang X, Zhang C, Xue L, Yang L. Expression and clinical significance of MAPK and EGFR in triple-negative breast cancer. Oncol Lett 2020; 19:1842-1848. [PMID: 32194678 PMCID: PMC7038935 DOI: 10.3892/ol.2020.11274] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 09/27/2019] [Indexed: 12/26/2022] Open
Abstract
To investigate the expression and clinical significance of mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) in triple-negative breast cancer (TNBC), a total of 300 TNBC and 120 paired paracancerous tissues were examined. Immunohistochemistry was conducted to determine the expression levels of MAPK and EGFR, and the correlation between MAPK and EGFR expression was evaluated using Cramer's V test. The association between MAPK and EGFR expression, and various clinicopathological variables (such as lymph node metastasis, clinical stage, recurrence and metastasis) was also evaluated, using the χ2 test. MAPK and EGFR expression levels in TNBC tissues were significantly higher than in the paired paracancerous tissues. Moreover, MAPK expression was associated with that of EGFR in TNBC tissues. The positive expression rates of MAPK and EGFR in patients with lymph node metastasis, advanced clinical stage, tumor recurrence and metastasis were higher than those without. Patients with positive expression of MAPK and EGFR in TNBC tissues had poorer prognoses and lower overall survival times than those without expression. In summary, the expression of MAPK and EGFR is closely associated with tumor invasion and the metastasis of TNBC, and may therefore be used as an indicator of poor prognosis in patients with TNBC.
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Affiliation(s)
- Weihua Jiang
- Department of Breast Surgery, The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, Xinjiang 830011, P.R. China
| | - Xiaowen Wang
- Department of Breast Surgery, The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, Xinjiang 830011, P.R. China
| | - Chenguang Zhang
- Department of Breast Surgery, The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, Xinjiang 830011, P.R. China
| | - Laiti Xue
- Department of Breast Surgery, The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, Xinjiang 830011, P.R. China
| | - Liang Yang
- Department of Breast Surgery, The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, Xinjiang 830011, P.R. China
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Chandler BC, Moubadder L, Ritter CL, Liu M, Cameron M, Wilder-Romans K, Zhang A, Pesch AM, Michmerhuizen AR, Hirsh N, Androsiglio M, Ward T, Olsen E, Niknafs YS, Merajver S, Thomas DG, Brown PH, Lawrence TS, Nyati S, Pierce LJ, Chinnaiyan A, Speers C. TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination. J Clin Invest 2020; 130:958-973. [PMID: 31961339 PMCID: PMC6994133 DOI: 10.1172/jci130435] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 10/31/2019] [Indexed: 12/12/2022] Open
Abstract
Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Dafydd G. Thomas
- Rogel Cancer Center
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Powel H. Brown
- Department of Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Shyam Nyati
- Department of Radiation Oncology
- Rogel Cancer Center
| | | | - Arul Chinnaiyan
- Rogel Cancer Center
- Michigan Center for Translation Pathology
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - Corey Speers
- Department of Radiation Oncology
- Rogel Cancer Center
- Cancer Biology Program
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Schukken KM, Lin YC, Bakker PL, Schubert M, Preuss SF, Simon JE, van den Bos H, Storchova Z, Colomé-Tatché M, Bastians H, Spierings DC, Foijer F. Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition. Life Sci Alliance 2020; 3:3/2/e201900499. [PMID: 31980556 PMCID: PMC6985455 DOI: 10.26508/lsa.201900499] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 01/07/2020] [Accepted: 01/08/2020] [Indexed: 02/06/2023] Open
Abstract
Chromosomal instability (CIN) is a hallmark feature of cancer cells. In this study, Schukken and colleagues screen for compounds that selectively target CIN cells and identify an inhibitor of Src kinase to be selectively toxic for CIN cells. Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.
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Affiliation(s)
- Klaske M Schukken
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Yu-Chih Lin
- Goettingen Center for Molecular Biosciences and University Medical Center, Goettingen, Germany
| | - Petra L Bakker
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Michael Schubert
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stephanie F Preuss
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Judith E Simon
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Hilda van den Bos
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Zuzana Storchova
- Department of Molecular Genetics, University of Kaiserslautern, Germany
| | - Maria Colomé-Tatché
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.,Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Technical University of Munich, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Holger Bastians
- Goettingen Center for Molecular Biosciences and University Medical Center, Goettingen, Germany
| | - Diana Cj Spierings
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Floris Foijer
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Zhang L, Jiang B, Zhu N, Tao M, Jun Y, Chen X, Wang Q, Luo C. Mitotic checkpoint kinase Mps1/TTK predicts prognosis of colon cancer patients and regulates tumor proliferation and differentiation via PKCα/ERK1/2 and PI3K/Akt pathway. Med Oncol 2019; 37:5. [PMID: 31720873 DOI: 10.1007/s12032-019-1320-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 10/04/2019] [Indexed: 01/09/2023]
Abstract
Mps1/TTK plays an important role in development of many tumors. The purpose of the present study was designed to investigate the role of TTK in colon cancer. We analyzed TTK and colon cancer in the GEO database, colon cancer tissues and normal tissues were collected to verify the results by immunohistochemistry. We detected the TTK expression in the colon cancer cell lines, and overexpressed or silenced TTK expression in colon cancer cell lines. GEO database showed that the expression of TTK was higher in the colon cancer tissues than normal tissues, higher level of TTK shows unfavourable prognosis in colon patients. Furthermore, high differentiation of colon shows the lower expression of TTK. The higher expression of TTK links with the high microsatellite status. However, the expression of TTK has no significant difference among the different stages of colon cancer patients, and has no significant relationship with recurrence or relapse. Here, we also report that the differential expression of TTK in colon cancer cells alters the intrinsic negative regulation of cell proliferation and differentiation, resulting in the difference of proliferation and differentiation capacity. TTK could activate the PKCα/ERK1/2 to influence the proliferation and inactivate the PI3K/AKT pathway to inhibition the expression of MUC2 and TFF3 that related to the differentiation of colon cells. In conclusions, TTK promote the colon cancer cell proliferation via activation of PKCα/ERK1/2 and inhibit the differentiation via inactivation of PI3K/Akt pathway. TTK inhibition may be the potential therapeutic pathway for the treatment of colon cancer.
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Affiliation(s)
- Li Zhang
- Department of Central Laboratory and Huai'an Key Laboratory of Esophageal Cancer Biobank, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, 223300, China
| | - Baofei Jiang
- Department of Gastrointestinal Surgery, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huaian, 223300, Jiangsu, China
| | - Ni Zhu
- Department of Microbiology, Hubei University of Science and Technology, Xianning, 437100, Hubei, China
| | - Mingyue Tao
- Department of Central Laboratory and Huai'an Key Laboratory of Esophageal Cancer Biobank, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, 223300, China
| | - Yali Jun
- Department of Central Laboratory and Huai'an Key Laboratory of Esophageal Cancer Biobank, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, 223300, China
| | - Xiaofei Chen
- Department of Central Laboratory and Huai'an Key Laboratory of Esophageal Cancer Biobank, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, 223300, China.
| | - Qilong Wang
- Department of Central Laboratory and Huai'an Key Laboratory of Esophageal Cancer Biobank, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, 223300, China.
| | - Chao Luo
- Department of Central Laboratory and Huai'an Key Laboratory of Esophageal Cancer Biobank, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, Huai'an, 223300, China.
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Chen S, Wang J, Wang L, Peng H, Xiao L, Li C, Lin D, Yang K. Silencing TTK expression inhibits the proliferation and progression of prostate cancer. Exp Cell Res 2019; 385:111669. [PMID: 31605696 DOI: 10.1016/j.yexcr.2019.111669] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/12/2019] [Accepted: 10/03/2019] [Indexed: 12/27/2022]
Abstract
PURPOSE The main objective of our study was to explore changes in the expression levels of differentially expressed genes associated with prostate cancer progression and to design a series of experiments to verify the function of differentially expressed genes. METHOD The transcriptome datas of 499 cases of prostate cancer patients was downloaded from TCGA database. Differential genes associated with Gleason score were selected and filtered out by p < 0.05 and spearman coefficient >0.3. KEGG signaling pathway was enriched by differentially expressed genes, and TTK was selected as the research object. The expression of TTK was tested in prostate cancer tissues and prostate cancer cell lines. The changes of biological behavior of prostate cancer cell lines were verified after TTK was knocked out by siRNA and tumorigenic effect of TTK was verified by shRNA in vivo experiments. RESULT The expression of TTK was positively correlated with Gleason score of prostate cancer, and the expression of protein and mRNA in metastatic prostate cancer cell lines was higher than that in non-metastatic prostate cancer cell lines. Vitro biological experiments showed that TTK gene knockout could inhibit the proliferation, invasion and migration of PC3 and DU145 cells, and promote cell apoptosis. In vivo experiments showed that TTK knockout inhibited tumorigenesis in mice. It was found that the expression of CDK2 and CCNE1 decreased after TTK was knocked out. CONCLUSION Our results suggest that TTK is a gene associated with malignancy of PCa and could be a novel therapeutic target for clinical application.
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Affiliation(s)
- Saipeng Chen
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Jianan Wang
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Lin Wang
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Huahong Peng
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Longfei Xiao
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Changying Li
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Dong Lin
- Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada
| | - Kuo Yang
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
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