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1
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Soni N, Bacete L. The interplay between cell wall integrity and cell cycle progression in plants. PLANT MOLECULAR BIOLOGY 2023; 113:367-382. [PMID: 38091166 PMCID: PMC10730644 DOI: 10.1007/s11103-023-01394-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 11/30/2023] [Indexed: 12/20/2023]
Abstract
Plant cell walls are dynamic structures that play crucial roles in growth, development, and stress responses. Despite our growing understanding of cell wall biology, the connections between cell wall integrity (CWI) and cell cycle progression in plants remain poorly understood. This review aims to explore the intricate relationship between CWI and cell cycle progression in plants, drawing insights from studies in yeast and mammals. We provide an overview of the plant cell cycle, highlight the role of endoreplication in cell wall composition, and discuss recent findings on the molecular mechanisms linking CWI perception to cell wall biosynthesis and gene expression regulation. Furthermore, we address future perspectives and unanswered questions in the field, such as the identification of specific CWI sensing mechanisms and the role of CWI maintenance in the growth-defense trade-off. Elucidating these connections could have significant implications for crop improvement and sustainable agriculture.
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Affiliation(s)
- Nancy Soni
- Faculty of Natural Sciences, Institute for Biology, Norwegian University of Science and Technology, 5 Høgskoleringen, 7491, Trondheim, Norway
| | - Laura Bacete
- Faculty of Natural Sciences, Institute for Biology, Norwegian University of Science and Technology, 5 Høgskoleringen, 7491, Trondheim, Norway.
- Department of Plant Physiology, Umeå Plant Science Centre (UPSC), Umeå University, 901 87, Umeå, Sweden.
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2
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Forzisi E, Sesti F. Non-conducting functions of ion channels: The case of integrin-ion channel complexes. Channels (Austin) 2022; 16:185-197. [PMID: 35942524 PMCID: PMC9364710 DOI: 10.1080/19336950.2022.2108565] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Started as an academic curiosity more than two decades ago, the idea that ion channels can regulate cellular processes in ways that do not depend on their conducting properties (non-ionic functions) gained traction and is now a flourishing area of research. Channels can regulate physiological processes including actin cytoskeletal remodeling, cell motility, excitation-contraction coupling, non-associative learning and embryogenesis, just to mention some, through non-ionic functions. When defective, non-ionic functions can give rise to channelopathies involved in cancer, neurodegenerative disease and brain trauma. Ion channels exert their non-ionic functions through a variety of mechanisms that range from physical coupling with other proteins, to possessing enzymatic activity, to assembling with signaling molecules. In this article, we take stock of the field and review recent findings. The concept that emerges, is that one of the most common ways through which channels acquire non-ionic attributes, is by assembling with integrins. These integrin-channel complexes exhibit broad genotypic and phenotypic heterogeneity and reveal a pleiotropic nature, as they appear to be capable of influencing both physiological and pathological processes.
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Affiliation(s)
- Elena Forzisi
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
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3
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Chen M, Marrs B, Qi L, Knifley T, Weiss HL, D’Orazio JA, O’Connor KL. Integrin α6β4 signals through DNA damage response pathway to sensitize breast cancer cells to cisplatin. Front Oncol 2022; 12:1043538. [PMID: 36439467 PMCID: PMC9686853 DOI: 10.3389/fonc.2022.1043538] [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: 09/13/2022] [Accepted: 10/25/2022] [Indexed: 11/11/2022] Open
Abstract
Integrin α6β4 is highly expressed in triple negative breast cancer (TNBC) and drives its most aggressive traits; however, its impact on chemotherapeutic efficacy remains untested. We found that integrin α6β4 signaling promoted sensitivity to cisplatin and carboplatin but not to other chemotherapies tested. Mechanistic investigations revealed that integrin α6β4 stimulated the activation of ATM, p53, and 53BP1, which required the integrin β4 signaling domain. Genetic manipulation of gene expression demonstrated that mutant p53 cooperated with integrin α6β4 for cisplatin sensitivity and was necessary for downstream phosphorylation of 53BP1 and enhanced ATM activation. Additionally, we found that in response to cisplatin-induced DNA double strand break (DSB), integrin α6β4 suppressed the homologous recombination (HR) activity and enhanced non-homologous end joining (NHEJ) repair activity. Finally, we discovered that integrin α6β4 preferentially activated DNA-PK, facilitated DNA-PK-p53 and p53-53BP1 complex formation in response to cisplatin and required DNA-PK to enhance ATM, 53BP1 and p53 activation as well as cisplatin sensitivity. In summary, we discovered a novel function of integrin α6β4 in promoting cisplatin sensitivity in TNBC through DNA damage response pathway.
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Affiliation(s)
- Min Chen
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, United States
| | - Brock Marrs
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Lei Qi
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Teresa Knifley
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Heidi L. Weiss
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Department of Biostatistics, University of Kentucky, Lexington, KY, United States
| | - John A. D’Orazio
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Department of Pediatrics, University of Kentucky, Lexington, KY, United States
| | - Kathleen L. O’Connor
- Markey Cancer Center, University of Kentucky, Lexington, KY, United States
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, United States
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4
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Howard AGA, Uribe RA. Hox proteins as regulators of extracellular matrix interactions during neural crest migration. Differentiation 2022; 128:26-32. [PMID: 36228422 PMCID: PMC10802151 DOI: 10.1016/j.diff.2022.09.003] [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: 08/02/2022] [Revised: 09/23/2022] [Accepted: 09/25/2022] [Indexed: 01/19/2023]
Abstract
Emerging during embryogenesis, the neural crest are a migratory, transient population of multipotent stem cell that differentiates into various cell types in vertebrates. Neural crest cells arise along the anterior-posterior extent of the neural tube, delaminate and migrate along routes to their final destinations. The factors that orchestrate how neural crest cells undergo delamination and their subsequent sustained migration is not fully understood. This review provides a primer about neural crest epithelial-to-mesenchymal transition (EMT), with a special emphasis on the role of the Extracellular matrix (ECM), cellular effector proteins of EMT, and subsequent migration. We also summarize published findings that link the expression of Hox transcription factors to EMT and ECM modification, thereby implicating Hox factors in regulation of EMT and ECM remodeling during neural crest cell ontogenesis.
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Affiliation(s)
- Aubrey G A Howard
- BioSciences Department, Rice University, Houston, TX, 77005, USA; Biochemistry and Cell Biology Program, Rice University, Houston, TX, 77005, USA
| | - Rosa A Uribe
- BioSciences Department, Rice University, Houston, TX, 77005, USA; Biochemistry and Cell Biology Program, Rice University, Houston, TX, 77005, USA.
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5
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Che H, Selig M, Rolauffs B. Micro-patterned cell populations as advanced pharmaceutical drugs with precise functional control. Adv Drug Deliv Rev 2022; 184:114169. [PMID: 35217114 DOI: 10.1016/j.addr.2022.114169] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 11/29/2022]
Abstract
Human cells are both advanced pharmaceutical drugs and 'drug deliverers'. However, functional control prior to or after cell implantation remains challenging. Micro-patterning cells through geometrically defined adhesion sites allows controlling morphogenesis, polarity, cellular mechanics, proliferation, migration, differentiation, stemness, cell-cell interactions, collective cell behavior, and likely immuno-modulatory properties. Consequently, generating micro-patterned therapeutic cells is a promising idea that has not yet been realized and few if any steps have been undertaken in this direction. This review highlights potential therapeutic applications, summarizes comprehensively the many cell functions that have been successfully controlled through micro-patterning, details the established micro-pattern designs, introduces the available fabrication technologies to the non-specialized reader, and suggests a quality evaluation score. Such a broad review is not yet available but would facilitate the manufacturing of therapeutically patterned cell populations using micro-patterned cell-instructive biomaterials for improved functional control as drug delivery systems in the context of cells as pharmaceutical products.
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Affiliation(s)
- Hui Che
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215006, China
| | - Mischa Selig
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, D-79104 Freiburg, Germany
| | - Bernd Rolauffs
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany.
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6
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Grimm TM, Herbinger M, Krüger L, Müller S, Mayer TU, Hauck CR. Lockdown, a selective small-molecule inhibitor of the integrin phosphatase PPM1F, blocks cancer cell invasion. Cell Chem Biol 2022; 29:930-946.e9. [PMID: 35443151 DOI: 10.1016/j.chembiol.2022.03.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 03/04/2022] [Accepted: 03/23/2022] [Indexed: 12/18/2022]
Abstract
Phosphatase PPM1F is a regulator of cell adhesion by fine-tuning integrin activity and actin cytoskeleton structures. Elevated expression of this enzyme in human tumors is associated with high invasiveness, enhanced metastasis, and poor prognosis. Thus, PPM1F is a target for pharmacological intervention, yet inhibitors of this enzyme are lacking. Here, we use high-throughput screening to identify Lockdown, a reversible and non-competitive PPM1F inhibitor. Lockdown is selective for PPM1F, because this compound does not inhibit other protein phosphatases in vitro and does not induce additional phenotypes in PPM1F knockout cells. Importantly, Lockdown-treated glioblastoma cells fully re-capitulate the phenotype of PPM1F-deficient cells as assessed by increased phosphorylation of PPM1F substrates and corruption of integrin-dependent cellular processes. Ester modification yields LockdownPro with increased membrane permeability and prodrug-like properties. LockdownPro suppresses tissue invasion by PPM1F-overexpressing human cancer cells, validating PPM1F as a therapeutic target and providing an access point to control tumor cell dissemination.
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Affiliation(s)
- Tanja M Grimm
- Lehrstuhl Zellbiologie, Department of Biology, University of Konstanz, Maildrop 621, Universitätsstrasse 10, 78467 Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany
| | - Marleen Herbinger
- Lehrstuhl Zellbiologie, Department of Biology, University of Konstanz, Maildrop 621, Universitätsstrasse 10, 78467 Konstanz, Germany
| | - Lena Krüger
- Department of Chemistry, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany
| | - Silke Müller
- Lehrstuhl Molekulare Genetik, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany; Screening Center, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany
| | - Thomas U Mayer
- Lehrstuhl Molekulare Genetik, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany; Screening Center, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany
| | - Christof R Hauck
- Lehrstuhl Zellbiologie, Department of Biology, University of Konstanz, Maildrop 621, Universitätsstrasse 10, 78467 Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Universitätsstrasse 10, 78467 Konstanz, Germany.
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7
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Weiss F, Lauffenburger D, Friedl P. Towards targeting of shared mechanisms of cancer metastasis and therapy resistance. Nat Rev Cancer 2022; 22:157-173. [PMID: 35013601 PMCID: PMC10399972 DOI: 10.1038/s41568-021-00427-0] [Citation(s) in RCA: 159] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
Resistance to therapeutic treatment and metastatic progression jointly determine a fatal outcome of cancer. Cancer metastasis and therapeutic resistance are traditionally studied as separate fields using non-overlapping strategies. However, emerging evidence, including from in vivo imaging and in vitro organotypic culture, now suggests that both programmes cooperate and reinforce each other in the invasion niche and persist upon metastatic evasion. As a consequence, cancer cell subpopulations exhibiting metastatic invasion undergo multistep reprogramming that - beyond migration signalling - supports repair programmes, anti-apoptosis processes, metabolic adaptation, stemness and survival. Shared metastasis and therapy resistance signalling are mediated by multiple mechanisms, such as engagement of integrins and other context receptors, cell-cell communication, stress responses and metabolic reprogramming, which cooperate with effects elicited by autocrine and paracrine chemokine and growth factor cues present in the activated tumour microenvironment. These signals empower metastatic cells to cope with therapeutic assault and survive. Identifying nodes shared in metastasis and therapy resistance signalling networks should offer new opportunities to improve anticancer therapy beyond current strategies, to eliminate both nodular lesions and cells in metastatic transit.
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Affiliation(s)
- Felix Weiss
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, Netherlands
| | - Douglas Lauffenburger
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Peter Friedl
- Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, Netherlands.
- David H. Koch Center for Applied Research of Genitourinary Cancers, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Cancer Genomics Center, Utrecht, Netherlands.
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8
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Katsuno-Kambe H, Teo JL, Ju RJ, Hudson J, Stehbens SJ, Yap AS. Collagen polarization promotes epithelial elongation by stimulating locoregional cell proliferation. eLife 2021; 10:e67915. [PMID: 34661524 PMCID: PMC8550756 DOI: 10.7554/elife.67915] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 10/13/2021] [Indexed: 12/21/2022] Open
Abstract
Epithelial networks are commonly generated by processes where multicellular aggregates elongate and branch. Here, we focus on understanding cellular mechanisms for elongation using an organotypic culture system as a model of mammary epithelial anlage. Isotropic cell aggregates broke symmetry and slowly elongated when transplanted into collagen 1 gels. The elongating regions of aggregates displayed enhanced cell proliferation that was necessary for elongation to occur. Strikingly, this locoregional increase in cell proliferation occurred where collagen 1 fibrils reorganized into bundles that were polarized with the elongating aggregates. Applying external stretch as a cell-independent way to reorganize the extracellular matrix, we found that collagen polarization stimulated regional cell proliferation to precipitate symmetry breaking and elongation. This required β1-integrin and ERK signaling. We propose that collagen polarization supports epithelial anlagen elongation by stimulating locoregional cell proliferation. This could provide a long-lasting structural memory of the initial axis that is generated when anlage break symmetry.
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Affiliation(s)
- Hiroko Katsuno-Kambe
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneAustralia
| | - Jessica L Teo
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneAustralia
| | - Robert J Ju
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneAustralia
| | - James Hudson
- QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Samantha J Stehbens
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneAustralia
| | - Alpha S Yap
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneAustralia
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9
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Garlatti V, Lovisa S, Danese S, Vetrano S. The Multiple Faces of Integrin-ECM Interactions in Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:10439. [PMID: 34638778 PMCID: PMC8508809 DOI: 10.3390/ijms221910439] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 12/03/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) comprises a series of chronic and relapsing intestinal diseases, with Crohn's disease and ulcerative colitis being the most common. The abundant and uncontrolled deposition of extracellular matrix, namely fibrosis, is one of the major hallmarks of IBD and is responsible for the progressive narrowing and closure of the intestine, defined as stenosis. Although fibrosis is usually considered the product of chronic inflammation, the substantial failure of anti-inflammatory therapies to target and reduce fibrosis in IBD suggests that fibrosis might be sustained in an inflammation-independent manner. Pharmacological therapies targeting integrins have recently shown great promise in the treatment of IBD. The efficacy of these therapies mainly relies on their capacity to target the integrin-mediated recruitment and functionality of the immune cells at the damage site. However, by nature, integrins also act as mechanosensitive molecules involved in the intracellular transduction of signals and modifications originating from the extracellular matrix. Therefore, understanding integrin signaling in the context of IBD may offer important insights into mechanisms of matrix remodeling, which are uncoupled from inflammation and could underlie the onset and persistency of intestinal fibrosis. In this review, we present the currently available knowledge on the role of integrins in the etiopathogenesis of IBD, highlighting their role in the context of immune-dependent and independent mechanisms.
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Affiliation(s)
- Valentina Garlatti
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Pharmaceutical Sciences, University of Piemonte Orientale ‘A. Avogadro’, 28100 Novara, Italy
| | - Sara Lovisa
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Silvio Danese
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Stefania Vetrano
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
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10
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Mohamed MF, Wood SJ, Roy R, Reiser J, Kuzel TM, Shafikhani SH. Pseudomonas aeruginosa ExoT induces G1 cell cycle arrest in melanoma cells. Cell Microbiol 2021; 23:e13339. [PMID: 33821556 PMCID: PMC8277761 DOI: 10.1111/cmi.13339] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/19/2022]
Abstract
Recently, we demonstrated that Pseudomonas aeruginosa Exotoxin T (ExoT) employs two distinct mechanisms to induce potent apoptotic cytotoxicity in a variety of cancer cell lines. We further demonstrated that it can significantly reduce tumour growth in an animal model for melanoma. During these studies, we observed that melanoma cells that were transfected with ExoT failed to undergo mitosis, regardless of whether they eventually succumbed to ExoT-induced apoptosis or survived in ExoT's presence. In this report, we sought to investigate ExoT's antiproliferative activity in melanoma. We delivered ExoT into B16 melanoma cells by bacteria (to show necessity) and by transfection (to show sufficiency). Our data indicate that ExoT exerts a potent antiproliferative function in melanoma cells. We show that ExoT causes cell cycle arrest in G1 interphase in melanoma cells by dampening the G1/S checkpoint proteins. Our data demonstrate that both domains of ExoT; (the ADP-ribosyltransferase (ADPRT) domain and the GTPase activating protein (GAP) domain); contribute to ExoT-induced G1 cell cycle arrest in melanoma. Finally, we show that the ADPRT-induced G1 cell cycle arrest in melanoma cells likely involves the Crk adaptor protein. Our data reveal a novel virulence function for ExoT and further highlight the therapeutic potential of ExoT against cancer.
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Affiliation(s)
- Mohamed F. Mohamed
- Department of Medicine/ Division of Hematology/Oncology/Cell Therapy, Rush University Medical Center, Chicago, IL, USA
- Department of Bacteriology, Mycology and Immunology, Faculty of Veterinary Medicine, Beni-Suef University, Egypt
| | - Stephen J. Wood
- Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL, USA
| | - Ruchi Roy
- Department of Medicine/ Division of Hematology/Oncology/Cell Therapy, Rush University Medical Center, Chicago, IL, USA
| | - Jochen Reiser
- Department of Medicine/ Division of Hematology/Oncology/Cell Therapy, Rush University Medical Center, Chicago, IL, USA
| | - Timothy M. Kuzel
- Department of Medicine/ Division of Hematology/Oncology/Cell Therapy, Rush University Medical Center, Chicago, IL, USA
| | - Sasha H. Shafikhani
- Department of Medicine/ Division of Hematology/Oncology/Cell Therapy, Rush University Medical Center, Chicago, IL, USA
- Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL, USA
- Cancer Center, Rush University Medical Center, Chicago, IL, USA
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11
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Gough RE, Jones MC, Zacharchenko T, Le S, Yu M, Jacquemet G, Muench SP, Yan J, Humphries JD, Jørgensen C, Humphries MJ, Goult BT. Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1. J Biol Chem 2021; 297:100837. [PMID: 34118235 PMCID: PMC8260872 DOI: 10.1016/j.jbc.2021.100837] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.
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Affiliation(s)
| | - Matthew C Jones
- Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Thomas Zacharchenko
- Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Shimin Le
- Mechanobiology Institute, National University of Singapore, Singapore
| | - Miao Yu
- Mechanobiology Institute, National University of Singapore, Singapore
| | - Guillaume Jacquemet
- Faculty of Science and Engineering, Cell Biology Department, Åbo Akademi University, Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Ste P Muench
- School of Biomedical Sciences, Astbury Centre for Structural Biology, University of Leeds, Leeds, UK
| | - Jie Yan
- Mechanobiology Institute, National University of Singapore, Singapore; Department of Physics, National University of Singapore, Singapore
| | - Jonathan D Humphries
- Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Claus Jørgensen
- Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Martin J Humphries
- Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
| | - Benjamin T Goult
- School of Biosciences, University of Kent, Canterbury, Kent, UK.
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12
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Li CH, Chiu KL, Hsia TC, Shen TC, Chen LH, Yu CC, Mong MC, Chang WS, Tsai CW, Bau DAT. Significant Association of Cyclin D1 Promoter Genotypes With Asthma Susceptibility in Taiwan. In Vivo 2021; 35:2041-2046. [PMID: 34182479 DOI: 10.21873/invivo.12473] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/03/2021] [Accepted: 05/04/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM The molecular mechanisms underlying the association between cell cycle and asthma are poorly understood, and cyclin D1 (CCND1) is found to be upregulated in asthma airway smooth muscle. We investigated whether the most frequently examined functional variants in CCND1 determine asthma susceptibility. MATERIALS AND METHODS We genotyped 651 participants for single-nucleotide polymorphisms (SNPs) at rs9344 and rs678653 on CCND1 and assessed the association of these SNPs with asthma risk. RESULTS Significant differences were found in the distributions of genotypic (p=0.0064) and allelic (p=0.0021) frequencies of CCND1 rs9344. In addition, AG or GG carriers had 0.63- or 0.48-fold adjusted odds ratios for asthma risk (95%confidence intervals=0.48-0.92 and 0.22-0.78, respectively) than those who carried the AA wildtype. CONCLUSION Our results suggest that cell cycle regulation may play a role in asthma initiation and development, and the CCND1 rs9344 genotype may serve as an early detection marker for asthma.
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Affiliation(s)
- Chia-Hsiang Li
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Kuo-Liang Chiu
- Division of Chest Medicine, Department of Internal Medicine, Taichung Tzu Chi Hospital, Taichung, Taiwan, R.O.C.,School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan, R.O.C
| | - Te-Chun Hsia
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Te-Chun Shen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Li-Hsiou Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Division of Chest Medicine, Department of Internal Medicine, Taichung Tzu Chi Hospital, Taichung, Taiwan, R.O.C
| | - Chien-Chih Yu
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.,School of Pharmacy, China Medical University, Taichung, Taiwan, R.O.C
| | - Mei-Chin Mong
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan, R.O.C
| | - Wen-Shin Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Chia-Wen Tsai
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - DA-Tian Bau
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.; .,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C
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13
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Zhang D, Hugo W, Redublo P, Miao H, Bergsneider M, Wang MB, Kim W, Yong WH, Heaney AP. A human ACTH-secreting corticotroph tumoroid model: Novel Human ACTH-Secreting Tumor Cell in vitro Model. EBioMedicine 2021; 66:103294. [PMID: 33773184 PMCID: PMC8024915 DOI: 10.1016/j.ebiom.2021.103294] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models. METHODS To characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures. FINDINGS scRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months. INTERPRETATION Our human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD. FUNDING This work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation.
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Affiliation(s)
- Dongyun Zhang
- Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - Willy Hugo
- Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - Peter Redublo
- Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - Hui Miao
- Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - Marvin Bergsneider
- Departments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - Marilene B Wang
- Departments of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - Won Kim
- Departments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - William H Yong
- Departments of Pathology and Lab Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
| | - Anthony P Heaney
- Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States; Departments of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, United States.
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14
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Quaglia F, Krishn SR, Daaboul GG, Sarker S, Pippa R, Domingo-Domenech J, Kumar G, Fortina P, McCue P, Kelly WK, Beltran H, Liu Q, Languino LR. Small extracellular vesicles modulated by αVβ3 integrin induce neuroendocrine differentiation in recipient cancer cells. J Extracell Vesicles 2020; 9:1761072. [PMID: 32922691 PMCID: PMC7448905 DOI: 10.1080/20013078.2020.1761072] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The ability of small extracellular vesicles (sEVs) to reprogram cancer cells is well established. However, the specific sEV components able to mediate aberrant effects in cancer cells have not been characterized. Integrins are major players in mediating sEV functions. We have previously reported that the αVβ3 integrin is detected in sEVs of prostate cancer (PrCa) cells and transferred into recipient cells. Here, we investigate whether sEVs from αVβ3-expressing cells affect tumour growth differently than sEVs from control cells that do not express αVβ3. We compared the ability of sEVs to stimulate tumour growth, using sEVs isolated from PrCa C4-2B cells by iodixanol density gradient and characterized with immunoblotting, nanoparticle tracking analysis, immunocapturing and single vesicle analysis. We incubated PrCa cells with sEVs and injected them subcutaneously into nude mice to measure in vivo tumour growth or analysed in vitro their anchorage-independent growth. Our results demonstrate that a single treatment with sEVs shed from C4-2B cells that express αVβ3, but not from control cells, stimulates tumour growth and induces differentiation of PrCa cells towards a neuroendocrine phenotype, as quantified by increased levels of neuroendocrine markers. In conclusion, the expression of αVβ3 integrin generates sEVs capable of reprogramming cells towards an aggressive phenotype.
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Affiliation(s)
- Fabio Quaglia
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Shiv Ram Krishn
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - George G Daaboul
- Department of Research and Development, NanoView Biosciences, Boston, MA, USA
| | - Srawasti Sarker
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Raffaella Pippa
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Gaurav Kumar
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Paolo Fortina
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Peter McCue
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA
| | - William K Kelly
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Himisha Beltran
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Qin Liu
- Molecular and Cellular Oncogenesis Program, the Wistar Institute, Philadelphia, PA, USA
| | - Lucia R Languino
- Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
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15
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Chondroitin Sulfate Promotes the Proliferation of Keloid Fibroblasts Through Activation of the Integrin and Protein Kinase B Pathways. Int J Mol Sci 2020; 21:ijms21061955. [PMID: 32182995 PMCID: PMC7139995 DOI: 10.3390/ijms21061955] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 03/11/2020] [Indexed: 01/05/2023] Open
Abstract
Keloids are dermal fibroproliferative tumors that arise beyond the boundary of the original wound edges and invades adjacent tissue. Keloids are characterized by the extensive production of extracellular matrix (ECM) and abnormal fibroblast proliferation. Chondroitin sulfate (CS) is one of the major structural components of cartilage and ECM. Recently, we reported the over-accumulation of CS in keloid lesions. Keloid-derived fibroblasts (KFs) and normal dermal fibroblasts (NFs) were incubated with CS. The fibroblast proliferation rate was analyzed using a tetrazolium salt colorimetric assay. The activation of the intracellular signaling pathway was analyzed by Western blotting. Wortmannin, a PI3K inhibitor, and anti-integrin antibodies were tested to investigate the mechanism of the CS-induced cell proliferation. CS strongly stimulated the proliferation of KFs, but not NFs. The analysis of the intracellular signal transduction pathway revealed that the stimulation effect of CS on KF proliferation was due to the activation of the protein kinase B (AKT) pathway and that integrin α1 was responsible for this phenomenon. We revealed that CS probably activates the AKT pathway through integrin to induce KF proliferation. CS may be a novel clinical therapeutic target in keloids.
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16
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Gu M, Zheng W, Zhang M, Dong X, Zhao Y, Wang S, Jiang H, Liu L, Zheng X. Downregulation of RAI14 inhibits the proliferation and invasion of breast cancer cells. J Cancer 2019; 10:6341-6348. [PMID: 31772666 PMCID: PMC6856746 DOI: 10.7150/jca.34910] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 09/19/2019] [Indexed: 12/20/2022] Open
Abstract
Retinoic acid-induced 14 (RAI14) is involved in the development of different tumor types, however, its expression and biological function in breast cancer are yet unknown. In the current study, we demonstrated that RAI14 was highly expressed in breast cancer. The high expression of RAI14 is positively correlated with the malignant progression of breast cancer and suggests a worse prognosis. Further, we found that knockdown RAI14 inhibits the proliferation, migration and invasion of breast cancer cells by regulating cell cycle and EMT through Akt/Cyclin D1, MMP2, MMP9 and ZEB1/E-cadhrin/Vimentin pathway. These findings revealed a novel function for RAI14 in breast cancer progression and suggest that RAI14 may become a promising diagnostic and therapeutic target for breast cancer.
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Affiliation(s)
- Ming Gu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
| | - Wenhui Zheng
- Department of anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
| | - Mingdi Zhang
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People's Republic of China
| | - Xiaoshen Dong
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
| | - Yan Zhao
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
| | - Shuo Wang
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
| | - Haiyang Jiang
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
| | - Lu Liu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
| | - Xinyu Zheng
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.,Lab 1, Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China
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17
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Yao Y, Wang Y, Li L, Xiang X, Li J, Chen J, Liu Z, Huang S, Xiong J, Deng J. Down-regulation of interferon regulatory factor 2 binding protein 2 suppresses gastric cancer progression by negatively regulating connective tissue growth factor. J Cell Mol Med 2019; 23:8076-8089. [PMID: 31559693 PMCID: PMC6851004 DOI: 10.1111/jcmm.14677] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 08/24/2019] [Indexed: 12/16/2022] Open
Abstract
Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional repressor involved in regulating gene expression and other biological processes, including tumorigenesis. However, the clinical significance and roles of IRF2BP2 in human gastric cancer (GC) remain uncertain. Clinical GC tissues were obtained from GC patients at the First Affiliated Hospital of Nanchang University. Immunohistochemistry (IHC) was conducted to detect the IRF2BP2 protein in clinical paraffin specimens. Cell proliferation, migration and invasion were evaluated by MTT, colony formation assays and transwell assays. Co-immunoprecipitation was conducted to detect the interaction between TEA domain family members 4 (TEAD4) and vestigial-like family member 4 (VGLL4) or Yes-associated protein 1 (YAP1). Dual-luciferase reporter assay was used to confirm the binding of miR-101-3p to the 3'-UTR. The expression of IRF2BP2 was significantly higher in GC tissues than in normal tissues. Patients with higher IRF2BP2 protein expression had lower survival. IRF2BP2 knockdown inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in GC cells. IRF2BP2 knockdown decreased the mRNA and protein levels of connective tissue growth factor (CTGF). The interaction between IRF2BP2 and VGLL4 increased the binding of TEAD4 to YAP1, resulting in the transcriptional coactivation of CTGF. In addition, miR-101-3p suppressed the expression of CTGF by directly targeting the 3'-UTR of IRF2BP2. Taken together, these findings provide a model for the role of miR-101-3p-IRF2BP2-CTGF signalling axis in GC and a novel insight into the mechanism of GC progression and metastasis.
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Affiliation(s)
- Yangyang Yao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yi Wang
- Radiotherapy＆Chemotherapy Department, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang Province, China
| | - Li Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Xiaojun Xiang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Junhe Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jun Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Zhen Liu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Shanshan Huang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jun Deng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
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18
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Wen P, Hu TG, Wen Y, Linhardt RJ, Zong MH, Zou YX, Wu H. Targeted delivery of phycocyanin for the prevention of colon cancer using electrospun fibers. Food Funct 2019; 10:1816-1825. [PMID: 30806395 DOI: 10.1039/c8fo02447b] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Phycocyanin (PC), a water-soluble biliprotein, exhibits potent anti-colon cancer properties. However, its application in functional foods is limited by the poor stability and low bioavailability of PC. In this study, we successfully encapsulated PC by coaxial electrospinning. The colon targeted release of PC was achieved with retention of the antioxidant activity of PC. The PC-loaded electrospun fiber mat (EFM) obtained inhibited HCT116 cell growth in a dose-dependent and time-dependent manner. In particular, the PC-loaded EFM exerted its anti-cancer activity by blocking the cell cycle at the G0/G1 phase and inducing cell apoptosis involving the decrease of Bcl-2/Bax, activation of caspase 3 and release of cytochrome c. This study suggests that co-axial electrospinning is an efficient and effective way to deliver PC and improve its bioavailability; thus, it represents a promising approach for encapsulating functional ingredients for colon cancer prevention.
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Affiliation(s)
- Peng Wen
- School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China.
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19
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Tang S, Chen S, Huang B, Jiang J, Wen J, Deng Y. Deoxynivalenol induces inhibition of cell proliferation via the Wnt/β-catenin signaling pathway. Biochem Pharmacol 2019; 166:12-22. [DOI: 10.1016/j.bcp.2019.05.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 05/06/2019] [Indexed: 12/13/2022]
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20
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Emmert H, Culley J, Brunton VG. Inhibition of cyclin-dependent kinase activity exacerbates H 2 O 2 -induced DNA damage in Kindler syndrome keratinocytes. Exp Dermatol 2019; 28:1074-1078. [PMID: 31260568 DOI: 10.1111/exd.14000] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 06/17/2019] [Accepted: 06/21/2019] [Indexed: 12/12/2022]
Abstract
Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.
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Affiliation(s)
- Hila Emmert
- Edinburgh Cancer Research UK Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Jayne Culley
- Edinburgh Cancer Research UK Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Valerie G Brunton
- Edinburgh Cancer Research UK Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
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21
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Martínez-Moreno D, Jiménez G, Gálvez-Martín P, Rus G, Marchal JA. Cartilage biomechanics: A key factor for osteoarthritis regenerative medicine. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1067-1075. [PMID: 30910703 DOI: 10.1016/j.bbadis.2019.03.011] [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: 11/18/2018] [Revised: 03/18/2019] [Accepted: 03/20/2019] [Indexed: 11/26/2022]
Abstract
Osteoarthritis (OA) is a joint disorder that is highly extended in the global population. Several researches and therapeutic strategies have been probed on OA but without satisfactory long-term results in joint replacement. Recent evidences show how the cartilage biomechanics plays a crucial role in tissue development. This review describes how physics alters cartilage and its extracellular matrix (ECM); and its role in OA development. The ECM of the articular cartilage (AC) is widely involved in cartilage turnover processes being crucial in regeneration and joint diseases. We also review the importance of physicochemical pathways following the external forces in AC. Moreover, new techniques probed in cartilage tissue engineering for biomechanical stimulation are reviewed. The final objective of these novel approaches is to create a cellular implant that maintains all the biochemical and biomechanical properties of the original tissue for long-term replacements in patients with OA.
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Affiliation(s)
- D Martínez-Moreno
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Spain
| | - G Jiménez
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada E-18071, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada E-18016, Spain
| | - P Gálvez-Martín
- Advanced Therapies Area, Pharmascience Division, Bioibérica S.A.U., E-08029 Barcelona, Spain; Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Granada E-18071, Spain
| | - G Rus
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Spain; Department of Structural Mechanics, University of Granada, Politécnico de Fuentenueva, Granada E-18071, Spain.
| | - J A Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Spain; Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada E-18071, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada E-18016, Spain.
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22
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Aryl-urea fatty acids that activate the p38 MAP kinase and down-regulate multiple cyclins decrease the viability of MDA-MB-231 breast cancer cells. Eur J Pharm Sci 2019; 129:87-98. [DOI: 10.1016/j.ejps.2018.12.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 12/03/2018] [Accepted: 12/21/2018] [Indexed: 01/07/2023]
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23
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Barui A, Datta P. Biophysical factors in the regulation of asymmetric division of stem cells. Biol Rev Camb Philos Soc 2018; 94:810-827. [PMID: 30467934 DOI: 10.1111/brv.12479] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 10/14/2018] [Accepted: 10/18/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Ananya Barui
- Centre for Healthcare Science and TechnologyIndian Institute of Engineering Science and Technology, Shibpur Howrah West Bengal 711103 India
| | - Pallab Datta
- Centre for Healthcare Science and TechnologyIndian Institute of Engineering Science and Technology, Shibpur Howrah West Bengal 711103 India
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24
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Vianay B, Senger F, Alamos S, Anjur-Dietrich M, Bearce E, Cheeseman B, Lee L, Théry M. Variation in traction forces during cell cycle progression. Biol Cell 2018; 110:91-96. [DOI: 10.1111/boc.201800006] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 01/21/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Benoit Vianay
- University of Paris Diderot; INSERM; CEA; Hôpital Saint Louis; Institut Universitaire d'Hematologie; UMRS1160; CytoMorpho Lab; 75010 Paris France
| | - Fabrice Senger
- University of Grenoble-Alpes; CEA; CNRS; INRA; Biosciences & Biotechnology Institute of Grenoble; Laboratoire de Phyiologie Cellulaire & Végétale; CytoMorpho Lab; 38054 Grenoble France
| | - Simon Alamos
- Physiology Course; Marine Biology Laboratory; Woods Hole MA USA
| | | | | | - Bevan Cheeseman
- Physiology Course; Marine Biology Laboratory; Woods Hole MA USA
| | - Lisa Lee
- Physiology Course; Marine Biology Laboratory; Woods Hole MA USA
| | - Manuel Théry
- University of Paris Diderot; INSERM; CEA; Hôpital Saint Louis; Institut Universitaire d'Hematologie; UMRS1160; CytoMorpho Lab; 75010 Paris France
- University of Grenoble-Alpes; CEA; CNRS; INRA; Biosciences & Biotechnology Institute of Grenoble; Laboratoire de Phyiologie Cellulaire & Végétale; CytoMorpho Lab; 38054 Grenoble France
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25
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Modica TME, Maiorani O, Sartori G, Pivetta E, Doliana R, Capuano A, Colombatti A, Spessotto P. The extracellular matrix protein EMILIN1 silences the RAS-ERK pathway via α4β1 integrin and decreases tumor cell growth. Oncotarget 2018; 8:27034-27046. [PMID: 28177903 PMCID: PMC5432316 DOI: 10.18632/oncotarget.15067] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 01/09/2017] [Indexed: 01/29/2023] Open
Abstract
The extracellular matrix plays a fundamental role in physiological and pathological proliferation. It exerts its function through a signal cascade starting from the integrins that take direct contact with matrix constituents most of which behave as pro-proliferative clues. On the contrary, EMILIN1, a glycoprotein interacting with the α4β1 integrin through its gC1q domain, plays a paradigmatic anti-proliferative role. Here, we demonstrate that the EMILIN1-α4 interaction de-activates the MAPK pathway through HRas. Epithelial cells expressing endogenous α4 integrin and persistently plated on gC1q inhibited pERK1/2 increasing HRasGTP and especially the HRasGTP ubiquitinated form (HRasGTP-Ub). The drug salirasib reversed this effect. In addition, only the gC1q-ligated α4 integrin chain co-immunoprecipitated the ubiquitinated HRas. Only epithelial cells transfected with the wild type form of the α4 integrin chain showed the EMILIN1/α4β1/HRas/pERK1/2 link, whereas cells transfected with a α4 integrin chain carrying a truncated cytoplasmic tail had no effect. In this study we unveiled the pathway activated by the gC1q domain of EMILIN1 through α4β1 integrin engagement and leading to the decrease of proliferation in an epithelial system.
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Affiliation(s)
- Teresa Maria Elisa Modica
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
| | - Orlando Maiorani
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
| | - Giulio Sartori
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
| | - Eliana Pivetta
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
| | - Roberto Doliana
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
| | - Alessandra Capuano
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
| | - Alfonso Colombatti
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
| | - Paola Spessotto
- Department of Translational Research, Experimental Oncology 2 Division, CRO Aviano, National Cancer Institute, Aviano, PN 33081, Italy
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26
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Gene expression profiles and molecular mechanism of cultured human chondrocytes' exposure to T-2 toxin and deoxynivalenol. Toxicon 2017; 140:38-44. [PMID: 28684119 DOI: 10.1016/j.toxicon.2017.06.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 06/21/2017] [Accepted: 06/28/2017] [Indexed: 12/11/2022]
Abstract
T-2 toxin and deoxynivalenol (DON) are secondary metabolites produced by Fusarium fungi and are commonly found on food and feed. Although T-2 toxin and DON have been suggested as the etiology of Kashin-Beck disease (KBD), an endemic osteochondropathy, little is known about the mechanism when human chondrocytes are exposed to T-2 toxin and DON. The purpose of this study is to identify the gene expression differences and underlying molecular changes modulated by T-2 toxin and DON in vitro in human chondrocytes. After the experiments of cell viability, the gene expression profiles were analyzed in cells that were treated with 0.01 μg/ml T-2 toxin and 1.0 μg/ml DON for 72 h by Affymetrix Human Gene Chip. The array results showed that 882 and 2118 genes were differentially expressed for T-2 toxin and DON exposure, respectively. Enrichment analysis revealed that diverse cellular processes including DNA damage, cell cycle regulation and metabolism of extracellular matrix were affected when human chondrocytes were exposed to T-2 toxin and DON. These results demonstrate the gene expression differences and molecular mechanism of cultured human chondrocytes exposure to T-2 toxin and DON, and provide a new insight into future research in the etiology of KBD.
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27
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Moreno-Layseca P, Ucar A, Sun H, Wood A, Olabi S, Gilmore AP, Brennan K, Streuli CH. The requirement of integrins for breast epithelial proliferation. Eur J Cell Biol 2017; 96:227-239. [PMID: 28363396 DOI: 10.1016/j.ejcb.2017.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 02/24/2017] [Accepted: 03/09/2017] [Indexed: 12/23/2022] Open
Abstract
Epithelial cells forming mammary gland ducts and alveoli require adhesion to the extracellular matrix for their function. Mammary epithelial cells need β1-integrins for normal cell cycle regulation. However, the role of β1-integrins in tumorigenesis has not been fully resolved. β1-integrin is necessary for tumour formation in transgenic mice expressing the Polyomavirus Middle T antigen, but it is dispensable in those overexpressing ErbB2. This suggests that some oncogenes can manage without β1-integrin to proliferate and form tumours, while others still require it. Here we have developed a model to test whether expression of an oncogene can surpass the need for β1-integrin to drive proliferation. We co-expressed the ErbB2 or Akt oncogenes with shRNA to target β1-integrin in mammary epithelial cells, and found that they show a differential dependence on β1-integrin for cell division. Moreover, we identified a key proliferative role of the Rac1-Pak axis downstream of β1-integrin signalling. Our data suggest that, in mammary epithelial cells, oncogenes with the ability to signal to Pak surpass the requirement of integrins for malignant transformation. This highlights the importance of using the correct combination therapy for breast cancer, depending on the oncogenes expressed in the tumour.
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Affiliation(s)
- Paulina Moreno-Layseca
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
| | - Ahmet Ucar
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
| | - Heyuan Sun
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
| | - Amber Wood
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
| | - Safiah Olabi
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom
| | - Andrew P Gilmore
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
| | - Keith Brennan
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
| | - Charles H Streuli
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
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28
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Inhibitory effect of NBL1 on PDGF-BB-induced human PASMC proliferation through blockade of PDGFβ-p38MAPK pathway. Biosci Rep 2016; 36:BSR20160199. [PMID: 27474499 PMCID: PMC5006314 DOI: 10.1042/bsr20160199] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 07/28/2016] [Indexed: 12/26/2022] Open
Abstract
Pulmonary artery remodelling is a key feature in the pathological progress of pulmonary arterial hypertension (PAH). Moreover, excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a critical role in the pathogenesis of pulmonary artery remodelling. Neuroblastoma suppressor of tumorigenicity 1 (NBL1) has been previously shown to induce growth inhibition in tumour cells. However, the effect of NBL1 in the regulation of human PASMC proliferation remains unclear. In cultured human PASMCs, we observed a dose-dependent inhibitory effect of NBL1 on platelet derived growth factor (PDGF)-BB-induced cell growth, DNA synthesis and proliferating cell nuclear antigen (PCNA) expression, as measured by MTS assay, 5-ethynil-2-deoxyuridine (EdU) analysis and western blots respectively. We also detected the expression and activities of cell-cycle positive regulators (cyclin D1, cyclin E, CDK2, CDK4 and CDK6) and negative regulators (p21 and p27) in human PASMCs by western blots and co-immuoprecipitation (IP). Our results show that NBL1-induced growth suppression is associated with the decreased activity of cyclin D1–CDK4 and the decreased phosphorylation of p27 in PDGF-BB-treated human PASMCs. By western blots using the phosphor-specific antibodies, we further demonstrated that NBL1 induced growth suppression is mediated by blockade of the up-stream PDGF-receptor β (PDGFRβ)-p38 mitogen-activated protein kinase (MAPK). In conclusion, our results suggest that NBL1 could inhibit PDGF-BB-induced human PASMC proliferation, and the underlying mechanism is associated with the decreased cyclin D1–CDK4 activity and up-regulated p27 by decreasing the phosphorylation of p27 via blockade of PDGFRβ-p38MAPK signal cascade. Our findings may provide a potential therapeutic target for PAH.
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29
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Synthesis and evaluation of (+)-decursin derivatives as inhibitors of the Wnt/β-catenin pathway. Bioorg Med Chem Lett 2016; 26:3529-32. [PMID: 27329797 DOI: 10.1016/j.bmcl.2016.06.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 06/07/2016] [Accepted: 06/10/2016] [Indexed: 10/21/2022]
Abstract
We synthesized (+)-decursin derivatives substituted with cinnamoyl- and phenyl propionyl groups originating from (+)-CGK062 and screened them using a cell-based assay to detect relative luciferase reporter activity. Of this series, compound 8b, in which a 3-acetoxy cinnamoyl group was introduced, most potently inhibited (97.0%) the Wnt/β-catenin pathway. Specifically, compound 8b dose-dependently inhibited Wnt3a-induced expression of the β-catenin response transcription (CRT) and increased β-catenin degradation in HEK293 reporter cells. Furthermore, compound 8b suppressed expression of the downstream β-catenin target genes cyclin D1 and c-myc and suppressed PC3 cell growth in a concentration-dependent manner.
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30
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Kamranvar SA, Gupta DK, Huang Y, Gupta RK, Johansson S. Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody. Oncotarget 2016; 7:30820-30. [PMID: 27127172 PMCID: PMC5058720 DOI: 10.18632/oncotarget.9003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 04/09/2016] [Indexed: 01/08/2023] Open
Abstract
Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells. Cancer cells acquire the ability to proliferate anchorage-independently, a characteristic feature of malignantly transformed cells. However, the molecular mechanisms underlying this escape of the normal control mechanisms remain unclear. The current study aimed to identify adhesion-induced reactions regulating the cytokinesis of non-transformed human fibroblasts.The adhesion-dependent control of cytokinesis was found to occur at a late stage close to the abscission, during which the endosomal sorting complex required for transport (ESCRT) severs the thin intercellular bridge connecting two nascent daughter cells. CEP55, a key protein involved in the abscission process, was localized at the midbody in both adherent and non-adherent fibroblasts, but it was unable to efficiently recruit ALIX, TSG101, and consequently the ESCRT-III subunit CHMP4B was missing in the non-adherent cells. PLK1, a kinase that prevents premature recruitment of CEP55 to the midbody, disappeared from this site more rapidly in the non-adherent cells. A FAK-Src signaling pathway downstream of integrin-mediated cell adhesion was found to decelerate both PLK1 degradation and CEP55 accumulation at the midbody. These data identify the regulation of PLK1 and CEP55 as steps where integrins exert control over the cytokinetic abscission.
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Affiliation(s)
- Siamak A. Kamranvar
- Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Deepesh Kumar Gupta
- Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Ying Huang
- Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Rajesh Kumar Gupta
- Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Staffan Johansson
- Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Uppsala, Sweden
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31
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McConnell EJ, Devapatla B, Yaddanapudi K, Davis KR. The soybean-derived peptide lunasin inhibits non-small cell lung cancer cell proliferation by suppressing phosphorylation of the retinoblastoma protein. Oncotarget 2016; 6:4649-62. [PMID: 25609198 PMCID: PMC4467105 DOI: 10.18632/oncotarget.3080] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 12/27/2014] [Indexed: 12/22/2022] Open
Abstract
Lunasin, a soybean bioactive peptide, has both chemopreventive and chemotherapeutic activities. The aim of this study was to determine the chemotherapeutic potential of lunasin against human lung cancer. Treatment of non-small cell lung cancer (NSCLC) cells with highly purified soybean-derived lunasin caused limited, cell-line specific anti-proliferative effects on anchorage-dependent growth whereas two normal bronchial epithelial cell lines were unaffected. Lunasin's antiproliferative effects were potentiated upon utilization of anchorage-independent conditions. Furthermore, NSCLC cell lines that were unaffected by lunasin in anchorage-dependent assays exhibited a dose-dependent inhibition in colony formation or colony size. Mouse xenograft studies revealed that 30 mg lunasin/kg body weight per day decreased NSCLC H1299 tumor volume by 63.0% at day 32. Mechanistic studies using cultured NSCLC H661 cells showed that lunasin inhibited cell cycle progression at the G1/S phase interface without inducing apoptosis. Immunoblot analyses of key cell-cycle proteins demonstrated that lunasin altered the expression of the G1 specific cyclin-dependent kinase complex components, increased levels of p27Kip1, reduced levels of phosphorylated Akt, and ultimately inhibited the sequential phosphorylation of the retinoblastoma protein (RB). These results establish for the first time that lunasin can inhibit NSCLC proliferation by suppressing cell-cycle dependent phosphorylation of RB.
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Affiliation(s)
- Elizabeth J McConnell
- Owensboro Cancer Research Program, Mitchell Memorial Cancer Center, Owensboro, Kentucky, USA
| | - Bharat Devapatla
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Kavitha Yaddanapudi
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.,Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Keith R Davis
- Owensboro Cancer Research Program, Mitchell Memorial Cancer Center, Owensboro, Kentucky, USA.,James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.,Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
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32
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Lu H, Gao F, Shu G, Xia G, Shao Z, Lu H, Cheng K. Wogonin inhibits the proliferation of myelodysplastic syndrome cells through the induction of cell cycle arrest and apoptosis. Mol Med Rep 2015; 12:7285-92. [PMID: 26398525 PMCID: PMC4626188 DOI: 10.3892/mmr.2015.4353] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 09/01/2015] [Indexed: 01/17/2023] Open
Abstract
The present study aimed to assess the effects of the flavonoid, wogonin, and its underlying mechanism on myelodysplastic syndrome (MDS) in SKM-1 cells. In the present study, wogonin inhibited the cell proliferation of SKM‑1 cells in a dose‑ and time‑dependent manner, with the concentration required to yield a half maximal inhibitory concentration (IC50) of 212.1 µmol/l at 24 h, and 43.4 µmol/l at 72 h. Furthermore, wogonin induced cell cycle arrest at the G0/G1 phase and induced the apoptosis of the SKM‑1 cells, which possibly accounted for the antiproliferative effects of wogonin. Notably, the data in the present study revealed that wogonin upregulated the expression of p21Cip1 and p27Kip1, and downregulated the expression of cyclin D1 and cyclin‑dependent kinase 4, causing a G0/G1 phase arrest, halting cell cycle progression, and inducing apoptosis in the MDS cells, which was mediated by the mitochondrial pathway through a modulation of the ratio of Bcl‑2 to Bax. Therefore, the present study suggests that wogonin may be a logical therapeutic target in the treatment of MDS.
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Affiliation(s)
- Huixia Lu
- Department of Clinical Laboratory Medicine of Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Feng Gao
- Department of Laboratory Medicine of Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Guofang Shu
- Department of Clinical Laboratory Medicine of Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Guohua Xia
- Department of Laboratory Medicine of Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Zeye Shao
- Department of Laboratory Medicine of Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Hangqin Lu
- Department of Laboratory Medicine of Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Keping Cheng
- Department of Clinical Laboratory Medicine of Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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33
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Integrin-specific hydrogels as adaptable tumor organoids for malignant B and T cells. Biomaterials 2015; 73:110-9. [PMID: 26406451 DOI: 10.1016/j.biomaterials.2015.09.007] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 09/07/2015] [Accepted: 09/09/2015] [Indexed: 01/21/2023]
Abstract
Non-Hodgkin lymphomas are a heterogeneous group of lymphoproliferative disorders of B and T cell origin that are treated with chemotherapy drugs with variable success rate that has virtually not changed over decades. Although new classes of chemotherapy-free epigenetic and metabolic drugs have emerged, durable responses to these conventional and new therapies are achieved in a fraction of cancer patients, with many individuals experiencing resistance to the drugs. The paucity in our understanding of what regulates the drug resistance phenotype and establishing a predictive indicator is, in great part, due to the lack of adequate ex vivo lymphoma models to accurately study the effect of microenvironmental cues in which malignant B and T cell lymphoma cells arise and reside. Unlike many other tumors, lymphomas have been neglected from biomaterials-based microenvironment engineering standpoint. In this study, we demonstrate that B and T cell lymphomas have different pro-survival integrin signaling requirements (αvβ3 and α4β1) and the presence of supporting follicular dendritic cells are critical for enhanced proliferation in three-dimensional (3D) microenvironments. We engineered adaptable 3D tumor organoids presenting adhesive peptides with distinct integrin specificities to B and T cell lymphoma cells that resulted in enhanced proliferation, clustering, and drug resistance to the chemotherapeutics and a new class of histone deacetylase inhibitor (HDACi), Panobinostat. In Diffuse Large B cell Lymphomas, the 3D microenvironment upregulated the expression level of B cell receptor (BCR), which supported the survival of B cell lymphomas through a tyrosine kinase Syk in the upstream BCR pathway. Our integrin specific ligand functionalized 3D organoids mimic a lymphoid neoplasm-like heterogeneous microenvironment that could, in the long term, change the understanding of the initiation and progression of hematological tumors, allow primary biospecimen analysis, provide prognostic values, and importantly, allow a faster and more rational screening and translation of therapeutic regimens.
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34
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Narasimhan K, Lee YM, Lim TK, Port SA, Han JH, Chen CS, Lin Q. Genistein exerts anti-leukemic effects on genetically different acute myeloid leukemia cell lines by inhibiting protein synthesis and cell proliferation while inducing apoptosis - molecular insights from an iTRAQ™ quantitative proteomics study. Oncoscience 2015; 2:111-124. [PMID: 25859554 PMCID: PMC4381704 DOI: 10.18632/oncoscience.120] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 02/05/2015] [Indexed: 12/29/2022] Open
Abstract
Acute myeloid leukemia (AML) is a form of cancer that affects the hematopoietic precursor cells with lethal effects. We investigated the prospect of using genistein as an effective alternate therapy for AML. A two-cell line model, one possessing the FLT3 gene with the ITD mutation (MV4−11) and the other with the wildtype FLT3 gene (HL−60) has been employed. Our 8−plexed iTRAQ™−based quantitative proteomics analysis together with various functional studies demonstrated that genistein exerts anti-leukemic effects on both the AML cell lines. Genistein treatment on the AML cells showed that the drug arrested the mTOR pathway leading to down−regulation of protein synthesis. Additionally, genistein treatment is found to induce cell death via apoptosis. Contrasting regulatory effects of genistein on the cell cycle of the two cell lines were also identified, with the induction of G2/M phase arrest in HL-60 cells but not in MV4−11 cells. Hence, our study highlights the potent anti-leukemic effect of genistein on AML cells irrespective of their genetic status. This suggests the potential use of genistein as an effective general drug therapy for AML patients.
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Affiliation(s)
- Karthik Narasimhan
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Yew Mun Lee
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Teck Kwang Lim
- Department of Biological Sciences, National University of Singapore, Singapore
| | | | - Jin-Hua Han
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Chien-Shing Chen
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Hematology and Oncology, School of Medicine, Loma Linda University, Loma Linda, California, United States of America
| | - Qingsong Lin
- Department of Biological Sciences, National University of Singapore, Singapore
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35
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Wang L, Wu J, Lu J, Ma R, Sun D, Tang J. Regulation of the cell cycle and PI3K/Akt/mTOR signaling pathway by tanshinone I in human breast cancer cell lines. Mol Med Rep 2014; 11:931-9. [PMID: 25355053 PMCID: PMC4262478 DOI: 10.3892/mmr.2014.2819] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 09/18/2014] [Indexed: 01/25/2023] Open
Abstract
Breast cancer is the second leading cause of cancer‑related mortality in females worldwide. Therefore, identifying alternative strategies to combat the disease mortality is important. The aim of the present study was to investigate the effect of tanshinone I (Tan I) on the tumorigenicity of estrogen‑responsive MCF‑7 and estrogen‑independent MDA‑MB‑453 human breast cancer cells. The cytotoxicity of Tan I was evaluated using a Cell Counting Kit‑8 assay, the apoptosis and cell cycle distribution were detected using flow cytometry and the cell morphology was observed using a fluorescence microscope. In addition, the cell cycle regulatory proteins and apoptosis‑associated proteins involved in the phosphatidylinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway were detected using western blot analysis using specific protein antibodies. The MCF‑7 and MDA‑MB‑453 cells were equally sensitive to Tan I regardless of their responsiveness to estrogen. Tan I exerted similar antiproliferative activities and induction of apoptosis, resulting in S phase arrest accompanied by decreases in cyclin B and increases in cyclin E and cyclin A proteins, which may have been associated with the upregulation of cyclin‑dependent kinase inhibitors p21Cip1 and p27Kip1. In addition, Tan I was found to downregulate anti‑apoptotic and upregulate associated apoptotic components of the PI3K/Akt/mTOR signaling pathway. Notably, treatment with the PI3K inhibitor, LY294002, decreased the levels of phosphorylated (p)‑PI3K, p‑Akt and p‑mTOR. These results clearly indicated that the mechanism of action of Tan I involved, at least partially, an effect on the PI3K/Akt/mTOR signaling pathway, providing new information for anticancer drug design and development.
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Affiliation(s)
- Li Wang
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, P.R. China
| | - Jianzhong Wu
- Department of General Surgery, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Jianwei Lu
- Department of General Surgery, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Rong Ma
- Department of General Surgery, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Dawei Sun
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, P.R. China
| | - Jinhai Tang
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, P.R. China
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36
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Du T, Ju G, Wu S, Cheng Z, Cheng J, Zou X, Zhang G, Miao S, Liu G, Zhu Y. Microvesicles derived from human Wharton's jelly mesenchymal stem cells promote human renal cancer cell growth and aggressiveness through induction of hepatocyte growth factor. PLoS One 2014; 9:e96836. [PMID: 24797571 PMCID: PMC4010513 DOI: 10.1371/journal.pone.0096836] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Accepted: 04/11/2014] [Indexed: 12/14/2022] Open
Abstract
In our previous study, microvesicles (MVs) released from human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) retard the growth of bladder cancer cells. We would like to know if MVs have a similar effect on human renal cell carcinoma (RCC). By use of cell culture and the BALB/c nu/nu mice xeno-graft model, the influence of MVs upon the growth and aggressiveness of RCC (786-0) was assessed. Cell counting kit-8 (CCK-8) assay, incidence of tumor, tumor size, Ki-67 or TUNEL staining was used to evaluate tumor cell growth in vitro or in vivo. Flow cytometry assay (in vitro) or examination of cyclin D1 expression (in vivo) was carried out to determine the alteration of cell cycle. The aggressiveness was analyzed by Wound Healing Assay (in vitro) or MMP-2 and MMP-9 expression (in vivo). AKT/p-AKT, ERK1/2/p-ERK1/2 or HGF/c-MET expression was detected by real-time PCR or western blot. Our data demonstrated that MVs promote the growth and aggressiveness of RCC both in vitro and in vivo. In addition, MVs facilitated the progression of cell cycle from G0/1 to S. HGF expression in RCC was greatly induced by MVs, associated with activation of AKT and ERK1/2 signaling pathways. RNase pre-treatment abrogated all effects of MVs. In summary, induction of HGF synthesis via RNA transferred by MVs activating AKT and ERK1/2 signaling is one of crucial contributors to the pro-tumor effect.
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Affiliation(s)
- Tao Du
- Department of Urology, Henan Provincial People's Hospital, Zhengzhou, P.R. China
| | - Guanqun Ju
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
- * E-mail: (GJ); (YZ)
| | - Shuai Wu
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
- Department of Urology, Qingdao Municipal Hospital, Qingdao, P.R. China
| | - Zhongliang Cheng
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Jun Cheng
- Department of Urology, Nantong Tongzhou People's Hospital, Jiangsu Province, P.R. China
| | - Xiangyu Zou
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Guangyuan Zhang
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Shuai Miao
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Guohua Liu
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Yingjian Zhu
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
- * E-mail: (GJ); (YZ)
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Wang HY, Yang SL, Liang HF, Li CH. HBx protein promotes oval cell proliferation by up-regulation of cyclin D1 via activation of the MEK/ERK and PI3K/Akt pathways. Int J Mol Sci 2014; 15:3507-18. [PMID: 24577313 PMCID: PMC3975350 DOI: 10.3390/ijms15033507] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 02/18/2014] [Accepted: 02/18/2014] [Indexed: 12/13/2022] Open
Abstract
Growing evidence has shown that hepatic oval cells, also named liver progenitor cells, play an important role in the process of liver regeneration in various liver diseases. Oval cell proliferation has been reported in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and chronic liver disease. Studies have found expression of HBV surface and core antigens in oval cells in the livers of patients with HCC, suggesting that HBV infection of oval cells could be a mechanism of human hepatocarcinogenesis. In addition, there is evidence of multiplication of HBV in oval cell culture. However, little research has been performed to explore the role of HBV-encoded proteins in the proliferation of hepatic oval cells. Previously, we successfully transfected the HBV x (HBx) gene, one of the four genes in the HBV genome, into a rat LE/6 oval cell line. In this study, we tested whether or not the transfected HBx gene could affect oval cell proliferation in vitro. Our results show that overexpression of HBx promotes the proliferation of oval cells and increases cyclin D1 expression, assessed at both the mRNA and protein levels. We also found that HBx activated the PI-3K/Akt and MEK/ERK1/2 pathways in HBx-transfected oval cells. Furthermore, the HBx-induced increases in cyclin D1 expression and oval cell proliferation were completely abolished by treatment with either MEK inhibitor PD184352 or PI-3K inhibitor LY294002. These results demonstrated that HBx has the ability to promote oval cell proliferation in vitro, and its stimulatory effects on cell proliferation and expression of cyclin D1 depend on the activation of the MEK/ERK and PI3K/Akt signaling pathways in cultured oval cells.
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Affiliation(s)
- Heng-Yi Wang
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Sheng-Li Yang
- Department of General Surgery, Liyuan Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430077, China.
| | - Hui-Fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China.
| | - Chang-Hai Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China.
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Cheng TY, Wu MS, Hua KT, Kuo ML, Lin MT. Cyr61/CTGF/Nov family proteins in gastric carcinogenesis. World J Gastroenterol 2014; 20:1694-1700. [PMID: 24587648 PMCID: PMC3930969 DOI: 10.3748/wjg.v20.i7.1694] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/07/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer-related death. The poor survival rate may reflect the relatively aggressive tumor biology of GC. Recently, the importance of the tumor microenvironment in carcinogenesis has emerged. In the tumor microenvironment, tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins capable of modulating carcinogenesis and regulating metastasis. The Cyr61/CTGF/Nov (CCN) proteins are a family of matricellular proteins with variable roles in many physiological and pathological processes. The evidence suggests that CCN family proteins contribute to GC carcinogenic processes. Here, we briefly review recent research on the effects of CCN family proteins in GC carcinogenesis and the development of new targeted agents in this field.
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Moreno-Layseca P, Streuli CH. Signalling pathways linking integrins with cell cycle progression. Matrix Biol 2014; 34:144-53. [DOI: 10.1016/j.matbio.2013.10.011] [Citation(s) in RCA: 158] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 10/22/2013] [Accepted: 10/22/2013] [Indexed: 12/30/2022]
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Wang H, Wu C, Wan S, Zhang H, Zhou S, Liu G. Shikonin attenuates lung cancer cell adhesion to extracellular matrix and metastasis by inhibiting integrin β1 expression and the ERK1/2 signaling pathway. Toxicology 2013; 308:104-12. [DOI: 10.1016/j.tox.2013.03.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 03/25/2013] [Accepted: 03/26/2013] [Indexed: 01/07/2023]
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Inhibition of pancreatic cancer cell growth in vivo using a tetracycline-inducible cyclin D1 antisense expression system. Pancreas 2013; 42:141-8. [PMID: 22722256 DOI: 10.1097/mpa.0b013e3182546de5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVES Cyclin D1 is important for pancreatic cancer growth. Our aim was to determine the effects of cyclin D1 inhibition on the growth of established pancreatic tumors. METHODS PANC-1 cells harboring cyclin D1 antisense cDNA in a tetracycline-inducible vector system were prepared. The effects of cyclin D1 inhibition after tumor development were characterized in a mouse model. RESULTS In vitro removal of tetracycline induced cyclin D1 antisense cDNA expression and inhibited cyclin D1 expression and cyclin D1-associated kinase activity as well as anchorage-dependent and -independent growth. After establishment of xenograft tumors in the presence of tetracycline (2 mg/mL) in the drinking water, animals were assigned to either control (tetracycline remained in the drinking water) or to the group without tetracycline for which tetracycline was removed from the drinking water. Tumor growth was significantly inhibited after removal of tetracycline. Microscopic analysis revealed that the area of central necrosis was significantly increased in the group without tetracycline paralleled by a reduction of the vital peripheral area of proliferating cells. CONCLUSIONS Our results confirmed that cyclin D1 plays an important role in the growth of pancreatic cancer cells and may be an attractive molecular target for the treatment of human pancreatic cancer.
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Kondo S, Iwata S, Yamada T, Inoue Y, Ichihara H, Kichikawa Y, Katayose T, Souta-Kuribara A, Yamazaki H, Hosono O, Kawasaki H, Tanaka H, Hayashi Y, Sakamoto M, Kamiya K, Dang NH, Morimoto C. Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer. Clin Cancer Res 2012; 18:6326-38. [PMID: 23037767 DOI: 10.1158/1078-0432.ccr-11-2162] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE In a substantial population of non-small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins. EXPERIMENTAL DESIGN Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs. RESULTS We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2Rγ(null) mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival. CONCLUSION Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis.
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Affiliation(s)
- Shunsuke Kondo
- Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan
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Vízkeleti L, Ecsedi S, Rákosy Z, Orosz A, Lázár V, Emri G, Koroknai V, Kiss T, Ádány R, Balázs M. The role of CCND1 alterations during the progression of cutaneous malignant melanoma. Tumour Biol 2012; 33:2189-99. [PMID: 23001925 DOI: 10.1007/s13277-012-0480-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 08/01/2012] [Indexed: 11/29/2022] Open
Abstract
It is well demonstrated that CCND1 amplification is a frequent event in the acral subtype of cutaneous malignant melanoma; however, its role in the other subtypes of the disease is still controversial. The objectives of this study were to evaluate genetic and expression alterations of CCND1 with a focus on primary cutaneous melanomas, to define BRAF and NRAS mutation status, and correlate the data with clinical-pathological parameters. CCND1 amplification was associated with ulceration and the localization of the metastasis. After correction for the mutation state of BRAF and NRAS genes, CCND1 amplification in samples without such mutations was associated with ulceration and sun exposure. The cyclin D1 (CCND1) mRNA level decreased in lesions with multiple metastases and was correlated with both the mRNA levels and mutation state of BRAF and NRAS genes. Primary melanomas with BRAF(V600) or NRAS(Q61 ) mutations exhibited lower CCND1 mRNA level. CCND1 protein expression was associated with Breslow thickness, metastasis formation, and shorter survival time. These observations suggest that CCND1 alterations are linked to melanoma progression and are modified by BRAF and NRAS mutations. Our data show that CCND1 amplification could have a prognostic relevance in cutaneous melanoma and highlight that altered CCND1 gene expression may influence the metastatic progression, survival, and the localization of metastases.
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Affiliation(s)
- Laura Vízkeleti
- Department of Preventive Medicine, Faculty of Public Health, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
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Kihira S, Yu EJ, Cunningham J, Cram EJ, Lee M. A novel mutation in β integrin reveals an integrin-mediated interaction between the extracellular matrix and cki-1/p27KIP1. PLoS One 2012; 7:e42425. [PMID: 22879977 PMCID: PMC3412830 DOI: 10.1371/journal.pone.0042425] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Accepted: 07/09/2012] [Indexed: 01/20/2023] Open
Abstract
The cell-extracellular matrix (ECM) interaction plays an essential role in maintaining tissue shapes and regulates cell behaviors such as cell adhesion, differentiation and proliferation. The mechanism by which the ECM influences the cell cycle in vivo is poorly understood. Here we demonstrate that the β integrin PAT-3 regulates the localization and expression of CKI-1, a C. elegans homologue of the cyclin dependent kinase inhibitor p27(KIP1). In nematodes expressing wild type PAT-3, CKI-1::GFP localizes primarily to nucleoli in hypodermal cells, whereas in animals expressing mutant pat-3 with a defective splice junction, CKI-1::GFP appears clumped and disorganized in nucleoplasm. RNAi analysis links cell adhesion genes to the regulation of CKI-1. RNAi of unc-52/perlecan, ina-1/α integrin, pat-4/ILK, and unc-97/PINCH resulted in abnormal CKI-1::GFP localization. Additional RNAi experiments revealed that the SCF E3 ubiquitin-ligase complex genes, skpt-1/SKP2, cul-1/CUL1 and lin-23/F-box, are required for the proper localization and expression of CKI-1, suggesting that integrin signaling and SCF E3 ligase work together to regulate the cellular distribution of CKI-1. These data also suggest that integrin plays a major role in maintaining proper CKI-1/p27(KIP1) levels in the cell. Perturbed integrin signaling may lead to the inhibition of SCF ligase activity, mislocalization and elevation of CKI-1/p27(KIP1). These results suggest that adhesion signaling is crucial for cell cycle regulation in vivo.
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Affiliation(s)
- Shingo Kihira
- Department of Biology, Baylor University, Waco, Texas, United States of America
| | - Eun Jeong Yu
- Department of Biology, Baylor University, Waco, Texas, United States of America
| | - Jessica Cunningham
- Department of Biology, Baylor University, Waco, Texas, United States of America
| | - Erin J. Cram
- Department of Biology, Northeastern University, Boston, Massachusetts, United States of America
| | - Myeongwoo Lee
- Department of Biology, Baylor University, Waco, Texas, United States of America
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Jeanes AI, Wang P, Moreno-Layseca P, Paul N, Cheung J, Tsang R, Akhtar N, Foster FM, Brennan K, Streuli CH. Specific β-containing integrins exert differential control on proliferation and two-dimensional collective cell migration in mammary epithelial cells. J Biol Chem 2012; 287:24103-12. [PMID: 22511753 PMCID: PMC3397837 DOI: 10.1074/jbc.m112.360834] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Understanding how cell cycle is regulated in normal mammary epithelia is essential for deciphering defects of breast cancer and therefore for developing new therapies. Signals provided by both the extracellular matrix and growth factors are essential for epithelial cell proliferation. However, the mechanisms by which adhesion controls cell cycle in normal epithelia are poorly established. In this study, we describe the consequences of removing the β1-integrin gene from primary cultures of mammary epithelial cells in situ, using CreER. Upon β1-integrin gene deletion, the cells were unable to progress efficiently through S-phase, but were still able to undergo collective two-dimensional migration. These responses are explained by the presence of β3-integrin in β1-integrin-null cells, indicating that integrins containing different β-subunits exert differential control on mammary epithelial proliferation and migration. β1-Integrin deletion did not inhibit growth factor signaling to Erk or prevent the recruitment of core adhesome components to focal adhesions. Instead the S-phase arrest resulted from defective Rac activation and Erk translocation to the nucleus. Rac inhibition prevented Erk translocation and blocked proliferation. Activated Rac1 rescued the proliferation defect in β1-integrin-depleted cells, indicating that this GTPase is essential in propagating proliferative β1-integrin signals. These results show that β1-integrins promote cell cycle in mammary epithelial cells, whereas β3-integrins are involved in migration.
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Affiliation(s)
- Alexa I Jeanes
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom
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Cantor JM, Ginsberg MH. CD98 at the crossroads of adaptive immunity and cancer. J Cell Sci 2012; 125:1373-82. [PMID: 22499670 DOI: 10.1242/jcs.096040] [Citation(s) in RCA: 136] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Adaptive immunity, a vertebrate specialization, adds memory and exquisite specificity to the basic innate immune responses present in invertebrates while conserving metabolic resources. In adaptive immunity, antigenic challenge requires extremely rapid proliferation of rare antigen-specific lymphocytes to produce large, clonally expanded effector populations that neutralize pathogens. Rapid proliferation and resulting clonal expansion are dependent on CD98, a protein whose well-conserved orthologs appear restricted to vertebrates. Thus, CD98 supports lymphocyte clonal expansion to enable protective adaptive immunity, an advantage that could account for the presence of CD98 in vertebrates. CD98 supports lymphocyte clonal expansion by amplifying integrin signals that enable proliferation and prevent apoptosis. These integrin-dependent signals can also provoke cancer development and invasion, anchorage-independence and the rapid proliferation of tumor cells. CD98 is highly expressed in many cancers and contributes to formation of tumors in experimental models. Strikingly, vertebrates, which possess highly conserved CD98 proteins, CD98-binding integrins and adaptive immunity, also display propensity towards invasive and metastatic tumors. In this Commentary, we review the roles of CD98 in lymphocyte biology and cancer. We suggest that the CD98 amplification of integrin signaling in adaptive immunity provides survival benefits to vertebrates, which, in turn, bear the price of increased susceptibility to cancer.
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Affiliation(s)
- Joseph M Cantor
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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Wang X, Liu Q, Ihsan A, Huang L, Dai M, Hao H, Cheng G, Liu Z, Wang Y, Yuan Z. JAK/STAT Pathway Plays a Critical Role in the Proinflammatory Gene Expression and Apoptosis of RAW264.7 Cells Induced by Trichothecenes as DON and T-2 Toxin. Toxicol Sci 2012; 127:412-24. [DOI: 10.1093/toxsci/kfs106] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Shroff K, Pearce TR, Kokkoli E. Enhanced integrin mediated signaling and cell cycle progression on fibronectin mimetic peptide amphiphile monolayers. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2012; 28:1858-1865. [PMID: 22149259 DOI: 10.1021/la203322t] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
In recent years, a variety of biomimetic constructs have emerged which mimic the bioactive sequences found in the natural extracellular matrix (ECM) proteins such as fibronectin (FN) that promote cell adhesion as well as proliferation on artificially functionalized interfaces. Much interest lies in investigating the ability of the ECM mimetic materials in regulating a number of vital cell functions including differentiation, gene expression, migration, and proliferation. A peptide amphiphile PR_b containing both the cell adhesive GRGDSP and synergistic PHSRN peptide sequences was developed in our group that was shown to support enhanced cell proliferation and ECM FN secretion as compared to GRGDSP and FN functionalized interfaces. In this study, we have investigated the binding affinity of the PR_b peptide ligand with the FN cell surface receptor, the α(5)β(1) integrin. We compared PR_b functionalized surfaces with FN and BSA coated surfaces and GRGDSP functionalized surfaces in terms of promoting intracellular signaling cascades that are essential for enhanced cellular activity. Specifically, we studied the phosphorylation of focal adhesion kinase (FAK) at tyrosine residues Y397 and Y576 and the formation of cyclin D1, both of which are intracellular markers of integrin mediated attachment of cells, signaling pathways, and progression of cell cycle. FAK and cyclin D1 encourage enhanced cell proliferation, differentiation, and gene expression. Our results show that the PR_b peptide ligand has a specific and strong binding affinity for the α(5)β(1) integrin with a dissociation constant of 76.3 ± 6.3 nM. The PR_b peptide ligands supported enhanced FAK phosphorylation activity and increased cyclin D1 formation as compared to the widely used GRGDSP ligand, the native protein FN (positive control), and BSA nonadhesive surfaces (negative control). These results encourage the use of the FN mimetic PR_b peptide in functionalizing biomaterials for potential tissue engineering and therapeutic applications.
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Affiliation(s)
- Kamlesh Shroff
- Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States
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Colombatti A, Spessotto P, Doliana R, Mongiat M, Bressan GM, Esposito G. The EMILIN/Multimerin family. Front Immunol 2012; 2:93. [PMID: 22566882 PMCID: PMC3342094 DOI: 10.3389/fimmu.2011.00093] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 12/21/2011] [Indexed: 01/12/2023] Open
Abstract
Elastin microfibrillar interface proteins (EMILINs) and Multimerins (EMILIN1, EMILIN2, Multimerin1, and Multimerin2) constitute a four member family that in addition to the shared C-terminus gC1q domain typical of the gC1q/TNF superfamily members contain a N-terminus unique cysteine-rich EMI domain. These glycoproteins are homotrimeric and assemble into high molecular weight multimers. They are predominantly expressed in the extracellular matrix and contribute to several cellular functions in part associated with the gC1q domain and in part not yet assigned nor linked to other specific regions of the sequence. Among the latter is the control of arterial blood pressure, the inhibition of Bacillus anthracis cell cytotoxicity, the promotion of cell death, the proangiogenic function, and a role in platelet hemostasis. The focus of this review is to highlight the multiplicity of functions and domains of the EMILIN/Multimerin family with a particular emphasis on the regulatory role played by the ligand-receptor interactions of the gC1q domain. EMILIN1 is the most extensively studied member both from the structural and functional point of view. The structure of the gC1q of EMILIN1 solved by NMR highlights unique characteristics compared to other gC1q domains: it shows a marked decrease of the contact surface of the trimeric assembly and while conserving the jelly-roll topology with two β-sheets of antiparallel strands it presents a nine-stranded β-sandwich fold instead of the usual 10-stranded fold. This is likely due to the insertion of nine residues that disrupt the ordered strand organization and forma a highly dynamic protruding loop. In this loop the residue E933 is the site of interaction between gC1q and the α4β1 and α9β1 integrins, and contrary to integrin occupancy that usually upregulates cell growth, when gC1q is ligated by the integrin the cells reduce their proliferative activity.
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Affiliation(s)
- Alfonso Colombatti
- Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico Aviano, Italy.
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Heo JS, Lee JC. β-Catenin mediates cyclic strain-stimulated cardiomyogenesis in mouse embryonic stem cells through ROS-dependent and integrin-mediated PI3K/Akt pathways. J Cell Biochem 2011; 112:1880-9. [PMID: 21433060 DOI: 10.1002/jcb.23108] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Wnt/β-catenin signaling regulates various cellular events involved in the proliferation and differentiation and these events are affected sensitively by applying to mechanical stimuli. However, the mechanisms by which mechanical force stimulates cardiomyogenesis are not extensively explored. In this study we investigated the cellular mechanisms by which β-catenin signaling regulates cardiac differentiation of strain-subjected embryonic stem (ES) cells. The application of cells to cyclic strain increased beating cardiomyocyte foci with the attendant increases of Cx 43 and Nkx 2.5 proteins. Anti-oxidants such as vitamin C or N-acetyl cysteine (NAC) blocked the strain-mediated increases of Cx 43, Nkx 2.5, and α5/β1 integrins. These anti-oxidants also suppressed the activation of phosphoinositide 3-kinase (PI3K) and Akt in cyclic strain-subjected cells. Western blot analysis revealed that PI3K is a critical downstream effector of β1 integrin signaling and mediates Cx 43 and Nkx 2.5 expression in cyclic strain-applied ES cells. Cyclic strain increased the expression of β-catenin and stimulated its nuclear translocation from the cytosol, which was prevented by anti-oxidant treatment. In addition, the application to cyclic strain increased mRNA expression of β-catenin target genes, Axin2 and c-myc, as well as the phosphorylation of glycogen synthase kinase-3β. Furthermore, the blockage of β-catenin by its specific siRNA transfection diminished the cellular levels of Cx 43 and Nkx 2.5 proteins and the number of beating cardiomyocyte foci. Collectively, these results suggest that β-catenin-mediated signaling is required for cyclic strain-stimulated cardiomyogenesis through ROS-dependent and integrin-mediated PI3K-Akt signaling cascades.
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Affiliation(s)
- Jung Sun Heo
- Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul 130-701, South Korea
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