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Menon AV, Song B, Chao L, Sriram D, Chansky P, Bakshi I, Ulianova J, Li W. Unraveling the future of genomics: CRISPR, single-cell omics, and the applications in cancer and immunology. Front Genome Ed 2025; 7:1565387. [PMID: 40292231 PMCID: PMC12021818 DOI: 10.3389/fgeed.2025.1565387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 03/26/2025] [Indexed: 04/30/2025] Open
Abstract
The CRISPR system has transformed many research areas, including cancer and immunology, by providing a simple yet effective genome editing system. Its simplicity has facilitated large-scale experiments to assess gene functionality across diverse biological contexts, generating extensive datasets that boosted the development of computational methods and machine learning/artificial intelligence applications. Integrating CRISPR with single-cell technologies has further advanced our understanding of genome function and its role in many biological processes, providing unprecedented insights into human biology and disease mechanisms. This powerful combination has accelerated AI-driven analyses, enhancing disease diagnostics, risk prediction, and therapeutic innovations. This review provides a comprehensive overview of CRISPR-based genome editing systems, highlighting their advancements, current progress, challenges, and future opportunities, especially in cancer and immunology.
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Affiliation(s)
- A. Vipin Menon
- Center for Genetic Medicine Research, Children’s National Hospital, Washington, DC, DC, United States
- Department of Genomics and Precision Medicine, George Washington University, Washington, DC, DC, United States
| | - Bicna Song
- Center for Genetic Medicine Research, Children’s National Hospital, Washington, DC, DC, United States
- Department of Genomics and Precision Medicine, George Washington University, Washington, DC, DC, United States
| | - Lumen Chao
- Center for Genetic Medicine Research, Children’s National Hospital, Washington, DC, DC, United States
- Department of Genomics and Precision Medicine, George Washington University, Washington, DC, DC, United States
| | - Diksha Sriram
- The George Washington University, Washington, DC, DC, United States
| | - Pamela Chansky
- Center for Genetic Medicine Research, Children’s National Hospital, Washington, DC, DC, United States
- Integrated Biomedical Sciences (IBS) Program, The George Washington University, Washington, DC, DC, United States
| | - Ishnoor Bakshi
- The George Washington University, Washington, DC, DC, United States
| | - Jane Ulianova
- Integrated Biomedical Sciences (IBS) Program, The George Washington University, Washington, DC, DC, United States
| | - Wei Li
- Center for Genetic Medicine Research, Children’s National Hospital, Washington, DC, DC, United States
- Department of Genomics and Precision Medicine, George Washington University, Washington, DC, DC, United States
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Wade EM, Goodin EA, Morgan T, Pereira S, Woolley AG, Jenkins ZA, Daniel PB, Robertson SP. The hinge-1 domain of Flna is not necessary for diverse physiological functions in mice. Eur J Clin Invest 2024; 54:e14308. [PMID: 39215762 DOI: 10.1111/eci.14308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION The filamins are cytoskeletal binding proteins that dynamically crosslink actin into orthogonal networks or bundle it into stress fibres. The domain structure of filamin proteins is very well characterised, with an N-terminal actin-binding region, followed by 24 immunoglobulin-like repeat units. The repeat domains are separated into distinct segments by two regions of low-complexity known as hinge-1 and hinge-2. The role of hinge-1 especially has been proposed to be essential for protein function as it provides flexibility to the otherwise rigid protein, and is a target for cleavage by calpain. Hinge-1 protects cells from otherwise destructive forces, and the products of calpain cleavage are involved in critical cellular signalling processes, such as survival during hypoxia. Pathogenic variants in FLNA encoding Filamin A, including those that remove the hinge-1 domain, cause a wide range of survivable developmental disorders. In contrast, complete loss of function of this gene is embryonic lethal in human and mouse. METHODS AND RESULTS In this study, we show that removing filamin A hinge-1 from mouse (FlnaΔH1), while preserving its expression level leads to no obvious developmental phenotype. Detailed characterisation of the skeletons of FlnaΔH1 mice showed no skeletal phenotype reminiscent of that found in the FLNA-causing skeletal dysplasia. Furthermore, nuclear functions of FLNA are maintained with loss of Filamin A hinge-1. CONCLUSION We conclude that hinge-1 is dispensable for filamin A protein function during development over the murine lifespan.
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Affiliation(s)
- Emma M Wade
- Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Elizabeth A Goodin
- Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Tim Morgan
- Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Stephana Pereira
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Adele G Woolley
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Maurice Wilkins Centre for Biodiscovery, University of Otago, Dunedin, New Zealand
| | - Zandra A Jenkins
- Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Philip B Daniel
- Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Stephen P Robertson
- Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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Altıntaş UB, Seo JH, Giambartolomei C, Ozturan D, Fortunato BJ, Nelson GM, Goldman SR, Adelman K, Hach F, Freedman ML, Lack NA. Decoding the epigenetics and chromatin loop dynamics of androgen receptor-mediated transcription. Nat Commun 2024; 15:9494. [PMID: 39489778 PMCID: PMC11532539 DOI: 10.1038/s41467-024-53758-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024] Open
Abstract
Androgen receptor (AR)-mediated transcription plays a critical role in development and prostate cancer growth. AR drives gene expression by binding to thousands of cis-regulatory elements (CRE) that loop to hundreds of target promoters. With multiple CREs interacting with a single promoter, it remains unclear how individual AR bound CREs contribute to gene expression. To characterize the involvement of these CREs, we investigate the AR-driven epigenetic and chromosomal chromatin looping changes by generating a kinetic multi-omic dataset comprised of steady-state mRNA, chromatin accessibility, transcription factor binding, histone modifications, chromatin looping, and nascent RNA. Using an integrated regulatory network, we find that AR binding induces sequential changes in the epigenetic features at CREs, independent of gene expression. Further, we show that binding of AR does not result in a substantial rewiring of chromatin loops, but instead increases the contact frequency of pre-existing loops to target promoters. Our results show that gene expression strongly correlates to the changes in contact frequency. We then propose and experimentally validate an unbalanced multi-enhancer model where the impact on gene expression of AR-bound enhancers is heterogeneous, and is proportional to their contact frequency with target gene promoters. Overall, these findings provide insights into AR-mediated gene expression upon acute androgen simulation and develop a mechanistic framework to investigate nuclear receptor mediated perturbations.
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Grants
- 221Z116 Türkiye Bilimsel ve Teknolojik Araştirma Kurumu (Scientific and Technological Research Council of Turkey)
- R01 CA259058 NCI NIH HHS
- R01 CA227237 NCI NIH HHS
- W81XWH-21-1-0339 U.S. Department of Defense (United States Department of Defense)
- R01 CA251555 NCI NIH HHS
- W81XWH-21-1-0234 U.S. Department of Defense (United States Department of Defense)
- PJT-173331 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
- W81XWH-22-1-0951 U.S. Department of Defense (United States Department of Defense)
- R01 CA262577 NCI NIH HHS
- N.A.L. was supported by funding from TUBITAK (221Z116), W81XWH-21-1-0234 (DoD), and CIHR PJT-173331.
- M.L.F. was supported by the Claudia Adams Barr Program for Innovative Cancer Research, the Dana-Farber Cancer Institute Presidential Initiatives Fund, the H.L. Snyder Medical Research Foundation, the Cutler Family Fund for Prevention and Early Detection, the Donahue Family Fund, W81XWH-21-1-0339, W81XWH-22-1-0951 (DoD), NIH Awards R01CA251555, R01CA227237, R01CA262577, R01CA259058 and a Movember PCF Challenge Award.
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Affiliation(s)
- Umut Berkay Altıntaş
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada
| | - Ji-Heui Seo
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Claudia Giambartolomei
- Integrative Data Analysis Unit, Health Data Science Centre, Human Technopole, Milan, 20157, Italy
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90024, USA
| | - Dogancan Ozturan
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada
| | - Brad J Fortunato
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Geoffrey M Nelson
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA
| | - Seth R Goldman
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
| | - Karen Adelman
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
- The Eli and Edythe L. Broad Institute, Boston, MA, 02142, USA
| | - Faraz Hach
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada
- Department of Computer Science, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Matthew L Freedman
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- The Eli and Edythe L. Broad Institute, Boston, MA, 02142, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Nathan A Lack
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
- Department of Medical Pharmacology, School of Medicine, Koç University, Istanbul, 34450, Turkey.
- Koç University Research Centre for Translational Medicine (KUTTAM), Koç University, 34450, Istanbul, Turkey.
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Wade EM, Morgan T, Gimenez G, Jenkins ZA, Titheradge H, O'Donnell M, Skidmore D, Suri M, Robertson SP. Pathogenic FLNA variants affecting the hinge region of filamin A are associated with male survival. Am J Med Genet A 2024; 194:e63779. [PMID: 38853608 DOI: 10.1002/ajmg.a.63779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 05/07/2024] [Accepted: 05/18/2024] [Indexed: 06/11/2024]
Abstract
Pathogenic variants in FLNA cause a diversity of X-linked developmental disorders associated with either preserved or diminished levels of filamin A protein and are conceptualized dichotomously as relating to underlying gain- or loss-of-function pathogenic mechanisms. Hemizygosity for germline deletions or truncating variants in FLNA is generally considered to result in embryonic lethality. Structurally, filamin A is composed of an N-terminal actin-binding region, followed by 24 immunoglobulin-like repeat units. The repeat domains are separated into distinct segments by two regions of low-complexity known as hinge-1 and hinge-2. Hinge-1 is proposed to confer flexibility to the otherwise rigid protein and is a target for cleavage by calpain with the resultant filamin fragments mediating crucial cellular signaling processes. Here, three families with pathogenic variants in FLNA that impair the function of hinge-1 in males are described, leading to distinct clinical phenotypes. One large in-frame deletion that includes the hinge leads to frontometaphyseal dysplasia in affected males and females, while two germline truncating variants located within the exon encoding hinge 1 result in phenotypes in males that are explained by exon skipping and under-expression of a transcript that deletes hinge-1 from the resultant protein. These three variants affecting hinge-1 indicate that this domain does not mediate cellular functions that, when deficientresult in embryonic lethality in males and that germline truncating variants in this region of FLNA can result in viable phenotypes in males.
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Affiliation(s)
- Emma M Wade
- Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand
| | - Tim Morgan
- Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand
| | - Gregory Gimenez
- Department of Pathology, Dunedin School of Medicine, Otago University, Dunedin, New Zealand
| | - Zandra A Jenkins
- Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand
| | - Hannah Titheradge
- Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Marie O'Donnell
- Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - David Skidmore
- IWK Hospital, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Mohnish Suri
- Clinical Genetics Service, City Hospital, Nottingham, UK
| | - Stephen P Robertson
- Department of Women's and Children's Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand
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Giovannelli P, Di Donato M, Licitra F, Sabbatino E, Tutino V, Castoria G, Migliaccio A. Filamin A in triple negative breast cancer. Steroids 2024; 205:109380. [PMID: 38311094 DOI: 10.1016/j.steroids.2024.109380] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/06/2024]
Abstract
Triple-negative breast cancer is a rare but highly heterogeneous breast cancer subtype with a limited choice of specific treatments. Chemotherapy remains the only efficient treatment, but its side effects and the development of resistance consolidate the urgent need to discover new targets. In TNBC, filamin A expression correlates to grade and TNM stage. Accordingly, this protein could constitute a new target for this BC subtype. Even if most of the data indicates its direct involvement in cancer progression, some contrasting results underline the need to deepen the studies. To elucidate a possible function of this protein as a TNBC marker, we summarized the main characteristic of filamin A and its involvement in physiological and pathological processes such as cancer. Lastly, we scrutinized its actions in triple-negative breast cancer and highlighted the need to increase the number of studies useful to better clarify the role of this versatile protein as a marker and target in TNBC, alone or in "collaboration" with other proteins with a relevant role in this BC subgroup.
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Affiliation(s)
- Pia Giovannelli
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy.
| | - Marzia Di Donato
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Fabrizio Licitra
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Emilia Sabbatino
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Viviana Tutino
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Antimo Migliaccio
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
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Di Donato M, Moretti A, Sorrentino C, Toro G, Gentile G, Iolascon G, Castoria G, Migliaccio A. Filamin A cooperates with the androgen receptor in preventing skeletal muscle senescence. Cell Death Discov 2023; 9:437. [PMID: 38040692 PMCID: PMC10692324 DOI: 10.1038/s41420-023-01737-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/06/2023] [Accepted: 11/21/2023] [Indexed: 12/03/2023] Open
Abstract
Aging induces a slow and progressive decrease in muscle mass and function, causing sarcopenia. Androgens control muscle trophism and exert important anabolic functions through the binding to the androgen receptor. Therefore, analysis of the androgen receptor-mediated actions in skeletal muscle might provide new hints for a better understanding of sarcopenia pathogenesis. In this study, we report that expression of the androgen receptor in skeletal muscle biopsies from 20 subjects is higher in young, as compared with old subjects. Co-immunoprecipitation experiments reveal that the androgen receptor is complexed with filamin A mainly in young, that in old subjects. Therefore, we have in depth analyzed the role of such complex using C2C12 myoblasts that express a significant amount of the androgen receptor. In these cells, hormone stimulation rapidly triggers the assembly of the androgen receptor/filamin A complex. Such complex prevents the senescence induced by oxidative stress in C2C12 cells, as disruption of the androgen receptor/filamin A complex by Rh-2025u stapled peptide re-establishes the senescent phenotype in C2C12 cells. Simultaneously, androgen stimulation of C2C12 cells rapidly triggers the activation of various signaling effectors, including Rac1, focal adhesion kinase, and mitogen-activated kinases. Androgen receptor blockade by bicalutamide or perturbation of androgen receptor/filamin A complex by Rh-2025u stapled peptide both reverse the hormone activation of signaling effectors. These findings further reinforce the role of the androgen receptor and its extranuclear partners in the rapid hormone signaling that controls the functions of C2C12 cells. Further investigations are needed to promote clinical interventions that might ameliorate muscle cell function as well the clinical outcome of age-related frailty.
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Affiliation(s)
- Marzia Di Donato
- Dipartimento di Medicina di Precisione, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 7-80138, Naples, Italy
| | - Antimo Moretti
- Dipartimento Multidisciplinare di Specialità Medico- Chirurgiche e Odontoiatriche, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 6-80138, Naples, Italy
| | - Carmela Sorrentino
- Dipartimento di Medicina di Precisione, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 7-80138, Naples, Italy
| | - Giuseppe Toro
- Dipartimento Multidisciplinare di Specialità Medico- Chirurgiche e Odontoiatriche, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 6-80138, Naples, Italy
| | - Giulia Gentile
- Dipartimento di Medicina di Precisione, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 7-80138, Naples, Italy
| | - Giovanni Iolascon
- Dipartimento Multidisciplinare di Specialità Medico- Chirurgiche e Odontoiatriche, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 6-80138, Naples, Italy
| | - Gabriella Castoria
- Dipartimento di Medicina di Precisione, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 7-80138, Naples, Italy.
| | - Antimo Migliaccio
- Dipartimento di Medicina di Precisione, Università della Campania 'L. Vanvitelli'- Via L. De Crecchio, 7-80138, Naples, Italy
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Aickareth J, Hawwar M, Sanchez N, Gnanasekaran R, Zhang J. Membrane Progesterone Receptors (mPRs/PAQRs) Are Going beyond Its Initial Definitions. MEMBRANES 2023; 13:membranes13030260. [PMID: 36984647 PMCID: PMC10056622 DOI: 10.3390/membranes13030260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/10/2023] [Accepted: 02/19/2023] [Indexed: 05/13/2023]
Abstract
Progesterone (PRG) is a key cyclical reproductive hormone that has a significant impact on female organs in vertebrates. It is mainly produced by the corpus luteum of the ovaries, but can also be generated from other sources such as the adrenal cortex, Leydig cells of the testes and neuronal and glial cells. PRG has wide-ranging physiological effects, including impacts on metabolic systems, central nervous systems and reproductive systems in both genders. It was first purified as an ovarian steroid with hormonal function for pregnancy, and is known to play a role in pro-gestational proliferation during pregnancy. The main function of PRG is exerted through its binding to progesterone receptors (nPRs, mPRs/PAQRs) to evoke cellular responses through genomic or non-genomic signaling cascades. Most of the existing research on PRG focuses on classic PRG-nPR-paired actions such as nuclear transcriptional factors, but new evidence suggests that PRG also exerts a wide range of PRG actions through non-classic membrane PRG receptors, which can be divided into two sub-classes: mPRs/PAQRs and PGRMCs. The review will concentrate on recently found non-classical membrane progesterone receptors (mainly mPRs/PAQRs) and speculate their connections, utilizing the present comprehension of progesterone receptors.
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Luthold C, Hallal T, Labbé DP, Bordeleau F. The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance? Cancers (Basel) 2022; 14:cancers14122887. [PMID: 35740556 PMCID: PMC9221142 DOI: 10.3390/cancers14122887] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 02/06/2023] Open
Abstract
Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers. While this process is increasingly well-characterized in breast cancer, a similar in-depth look at ECM stiffening remains lacking for prostate cancer. In this review, we scrutinize the current state of literature regarding ECM stiffening in prostate cancer and its potential association with disease progression and castration resistance.
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Affiliation(s)
- Carole Luthold
- Centre de Recherche sur le Cancer, Université Laval, Québec, QC G1R 3S3, Canada;
- Division of Oncology, Centre de Recherche du CHU de Québec-Université Laval, Hôtel-Dieu de Québec, Québec, QC G1R 3S3, Canada
| | - Tarek Hallal
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada;
| | - David P. Labbé
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada;
- Division of Urology, Department of Surgery, McGill University, Montréal, QC H4A 3J1, Canada
- Correspondence: (D.P.L.); (F.B.)
| | - François Bordeleau
- Centre de Recherche sur le Cancer, Université Laval, Québec, QC G1R 3S3, Canada;
- Division of Oncology, Centre de Recherche du CHU de Québec-Université Laval, Hôtel-Dieu de Québec, Québec, QC G1R 3S3, Canada
- Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Correspondence: (D.P.L.); (F.B.)
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Alsafadi DB, Abdullah MS, Bawadi R, Ahram M. The Association of RGS2 and Slug in the Androgen-induced Acquisition of Mesenchymal Features of Breast MDA-MB-453 Cancer Cells. Endocr Res 2022; 47:64-79. [PMID: 35168462 DOI: 10.1080/07435800.2022.2036752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) of tumor cells is a prerequisite to cancer cell invasion and metastasis. This process involves a network of molecular alterations. Androgen receptor (AR) plays an important role in the biology of breast cancers, particularly those dependent on AR expression like luminal AR (LAR) breast cancer subtype. We have recently reported that the AR agonist, dihydrotestosterone (DHT), induces a mesenchymal transition of MDA-MB-453 cells, concomitant with transcriptional up-regulation of Slug and regulator of G protein signaling 2 (RGS2). OBJECTIVE The role of Slug and RGS2 in mediating the DHT-induced effects in these cells was investigated. METHODS MDA-MB-453 cells were used as a model system of LAR breast cancer. Immunofluorescence was used to examine cell morphology and protein localization. Protein expression was analyzed by immunoblotting. Protein localization was confirmed by cell fractionation followed by immunoblotting. Protein-protein interaction was confirmed by co-immunoprecipitation followed by immunoblotting. Transwell membranes were used to assess cell migration. Transfection of cells with siRNA molecules that target Slug and RGS2 mRNA was utilized to delineate the modes of action of these two molecules. RESULTS Treatment of MDA-MB-453 cells with DHT induced the expression of both proteins. In addition, AR-Slug, AR-RGS2, and Slug-RGS2 interactions were observed shortly after AR activation. Knocking down Slug abrogated the basal, but not the DHT-induced, cell migration and blocked DHT-induced mesenchymal transition. On the other hand, RGS2 knocked-down cells had an increased level of Slug protein and assumed mesenchymal cell morphology with induced migration, and the addition of DHT further elongated cell morphology and stimulated their migration. Inhibition of AR or β-catenin reverted the RGS2 knocked-down cells to the epithelial phenotype, but only inhibition of AR blocked their DHT-induced migration. CONCLUSIONS These results suggest the involvement of RGS2 and Slug in a complex molecular network regulating the DHT-induced mesenchymal features in MDA-MB-453 cells. The study may offer a better understanding of the biological role of AR in breast cancer toward devising AR-based therapeutic strategies.
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Affiliation(s)
- Dana B Alsafadi
- Department of Microbiology, Pathology, and Forensic Medicine, School of Medicine, the University of Jordan, Amman, Jordan
| | - Mohammad S Abdullah
- Department of Microbiology, Pathology, and Forensic Medicine, School of Medicine, the University of Jordan, Amman, Jordan
| | - Randa Bawadi
- Department of Physiology and Biochemistry, School of Medicine, the University of Jordan, Amman, Jordan
| | - Mamoun Ahram
- Department of Physiology and Biochemistry, School of Medicine, the University of Jordan, Amman, Jordan
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Lu D, Song Y, Yu Y, Wang D, Liu B, Chen L, Li X, Li Y, Cheng L, Lv F, Zhang P, Xing Y. KAT2A-mediated AR translocation into nucleus promotes abiraterone-resistance in castration-resistant prostate cancer. Cell Death Dis 2021; 12:787. [PMID: 34381019 PMCID: PMC8357915 DOI: 10.1038/s41419-021-04077-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 11/24/2022]
Abstract
Abiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the androgen receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.
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Affiliation(s)
- Dingheng Lu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yarong Song
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ying Yu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Decai Wang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bing Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Liang Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xuexiang Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yunxue Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lulin Cheng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Fang Lv
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Pu Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yifei Xing
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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11
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The androgen receptor/filamin A complex as a target in prostate cancer microenvironment. Cell Death Dis 2021; 12:127. [PMID: 33500395 PMCID: PMC7838283 DOI: 10.1038/s41419-021-03402-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
Prostate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signaling pathways. Tumor microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumor area in androgen-treated 3D co-culture. The androgen receptor in association with β1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. This study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer.
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12
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Kelley CA, Triplett O, Mallick S, Burkewitz K, Mair WB, Cram EJ. FLN-1/filamin is required to anchor the actomyosin cytoskeleton and for global organization of sub-cellular organelles in a contractile tissue. Cytoskeleton (Hoboken) 2020; 77:379-398. [PMID: 32969593 DOI: 10.1002/cm.21633] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/11/2020] [Accepted: 09/17/2020] [Indexed: 01/01/2023]
Abstract
Actomyosin networks are organized in space, direction, size, and connectivity to produce coordinated contractions across cells. We use the C. elegans spermatheca, a tube composed of contractile myoepithelial cells, to study how actomyosin structures are organized. FLN-1/filamin is required for the formation and stabilization of a regular array of parallel, contractile, actomyosin fibers in this tissue. Loss of fln-1 results in the detachment of actin fibers from the basal surface, which then accumulate along the cell junctions and are stabilized by spectrin. In addition, actin and myosin are captured at the nucleus by the linker of nucleoskeleton and cytoskeleton complex (LINC) complex, where they form large foci. Nuclear positioning and morphology, distribution of the endoplasmic reticulum and the mitochondrial network are also disrupted. These results demonstrate that filamin is required to prevent large actin bundle formation and detachment, to prevent excess nuclear localization of actin and myosin, and to ensure correct positioning of organelles.
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Affiliation(s)
- Charlotte A Kelley
- Department of Biology, Northeastern University, Boston, Massachusetts, USA
| | - Olivia Triplett
- Department of Biology, Northeastern University, Boston, Massachusetts, USA
| | - Samyukta Mallick
- Department of Biology, Northeastern University, Boston, Massachusetts, USA
| | - Kristopher Burkewitz
- Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.,Department of Cell and Developmental Biology, Vanderbilt School of Medicine, Nashville, Tennessee, USA
| | - William B Mair
- Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Erin J Cram
- Department of Biology, Northeastern University, Boston, Massachusetts, USA
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13
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High fat diet causes distinct aberrations in the testicular proteome. Int J Obes (Lond) 2020; 44:1958-1969. [PMID: 32678325 PMCID: PMC7445115 DOI: 10.1038/s41366-020-0595-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 04/22/2020] [Accepted: 05/05/2020] [Indexed: 12/20/2022]
Abstract
Diet has important effects on normal physiology and the potential deleterious effects of high fat diets and obesity on male reproductive health are being increasingly described. We conducted a histological review of the effects of chronic high fat (HF) diet (using a mouse model fed a 45% fat diet for 21 weeks) with a discovery proteomic study to assess for changes in the abundance of proteins in the testis. Mice on a HF diet became obese and developed glucose intolerance. Using mass spectrometry, we identify 102 proteins affected in the testis of obese mice. These included structural proteins important for the blood testis barrier (filamin A, FLNA), proteins involved in oxidative stress responses (spermatogenesis associated 20, SPATA-20) and lipid homoeostasis (sterol regulatory element-binding protein 2, SREBP2 and apolipoprotein A1, APOA1). In addition, an important regulator protein paraspeckle component 1, PSPC-1, which interacts with the androgen receptor was significantly downregulated. Proteomic data was validated using both Western blotting and immunostaining which confirmed and localised protein expression in both mouse and human testis using biopsy specimens. This study focused mainly on the abnormalities that occurred at the protein level and as a result, we have identified several candidate proteins and conducted pathway analysis around the effects of HF diet on the testis providing novel insights not previously described. Some of the identified targets could be targeted therapeutically and future work is directed in this area.
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14
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Galardi A, Colletti M, Lavarello C, Di Paolo V, Mascio P, Russo I, Cozza R, Romanzo A, Valente P, De Vito R, Pascucci L, Peinado H, Carcaboso AM, Petretto A, Locatelli F, Di Giannatale A. Proteomic Profiling of Retinoblastoma-Derived Exosomes Reveals Potential Biomarkers of Vitreous Seeding. Cancers (Basel) 2020; 12:cancers12061555. [PMID: 32545553 PMCID: PMC7352325 DOI: 10.3390/cancers12061555] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/04/2020] [Accepted: 06/07/2020] [Indexed: 12/13/2022] Open
Abstract
Retinoblastoma (RB) is the most common tumor of the eye in early childhood. Although recent advances in conservative treatment have greatly improved the visual outcome, local tumor control remains difficult in the presence of massive vitreous seeding. Traditional biopsy has long been considered unsafe in RB, due to the risk of extraocular spread. Thus, the identification of new biomarkers is crucial to design safer diagnostic and more effective therapeutic approaches. Exosomes, membrane-derived nanovesicles that are secreted abundantly by aggressive tumor cells and that can be isolated from several biological fluids, represent an interesting alternative for the detection of tumor-associated biomarkers. In this study, we defined the protein signature of exosomes released by RB tumors (RBT) and vitreous seeding (RBVS) primary cell lines by high resolution mass spectrometry. A total of 5666 proteins were identified. Among these, 5223 and 3637 were expressed in exosomes RBT and one RBVS group, respectively. Gene enrichment analysis of exclusively and differentially expressed proteins and network analysis identified in RBVS exosomes upregulated proteins specifically related to invasion and metastasis, such as proteins involved in extracellular matrix (ECM) remodeling and interaction, resistance to anoikis and the metabolism/catabolism of glucose and amino acids.
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Affiliation(s)
- Angela Galardi
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
| | - Marta Colletti
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
- Correspondence: ; Tel.: +39-066859-3516
| | - Chiara Lavarello
- Core Facilities-Clinical Proteomics and Metabolomics, IRCCS, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genoa, Italy; (C.L.); (A.P.)
| | - Virginia Di Paolo
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
| | - Paolo Mascio
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
| | - Ida Russo
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
| | - Raffaele Cozza
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
| | - Antonino Romanzo
- Ophtalmology Unit, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’ Onofrio 4, 00165 Rome, Italy; (A.R.); (P.V.)
| | - Paola Valente
- Ophtalmology Unit, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’ Onofrio 4, 00165 Rome, Italy; (A.R.); (P.V.)
| | - Rita De Vito
- Department of Pathology, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza di Sant’ Onofrio 4, 00165 Rome, Italy;
| | - Luisa Pascucci
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo 4, 06126 Perugia, Italy;
| | - Hector Peinado
- Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, 28029 Madrid, Spain;
| | - Angel M. Carcaboso
- Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona, 08950 Esplugues de Llobregat, Spain;
| | - Andrea Petretto
- Core Facilities-Clinical Proteomics and Metabolomics, IRCCS, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genoa, Italy; (C.L.); (A.P.)
| | - Franco Locatelli
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
- Department of Ginecology/Obstetrics & Pediatrics, Sapienza University of Rome, 00185 Roma, Italy
| | - Angela Di Giannatale
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Rome, Italy; (A.G.); (V.D.P.); (P.M.); (I.R.); (R.C.); (F.L.); (A.D.G.)
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15
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Li XC, Huang CX, Wu SK, Yu L, Zhou GJ, Chen LJ. Biological roles of filamin a in prostate cancer cells. Int Braz J Urol 2019; 45:916-924. [PMID: 31268639 PMCID: PMC6844337 DOI: 10.1590/s1677-5538.ibju.2018.0535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 04/14/2019] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE This study aims to investigate the association of filamin A with the function and morphology of prostate cancer (PCa) cells, and explore the role of filamin A in the development of PCa, in order to analyze its significance in the evolvement of PCa. MATERIALS AND METHODS A stably transfected cell line, in which filamin A expression was suppressed by RNA interference, was first established. Then, the effects of the suppression of filamin A gene expression on the biological characteristics of human PCa LNCaP cells were observed through cell morphology, in vitro cell growth curve, soft agar cloning assay, and scratch test. RESULTS A cell line model with a low expression of filamin A was successfully constructed on the basis of LNCaP cells. The morphology of cells transfected with plasmid pSilencer-filamin A was the following: Cells were loosely arranged, had less connection with each other, had fewer tentacles, and presented a fibrous look. The growth rate of LNCap cells was faster than cells transfected with plasmid pSilencer-filamin A (P<0.05). The clones of LNCap cells in the soft agar cloning assay was significantly fewer than that of cells stably transfected with plasmid pSilencer-filamin A (P<0.05). Cells stably transfected with plasmid pSilencer-filamin A presented with a stronger healing and migration ability compared to LNCap cells (healing rate was 32.2% and 12.1%, respectively; P<0.05). CONCLUSION The expression of the filamin A gene inhibited the malignant development of LNCap cells. Therefore, the filamin A gene may be a tumor suppressor gene.
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Affiliation(s)
- Xue-Chao Li
- Department of Urologythe Fifth Medical CenterChinese PLA General HospitalBeijingChinaDepartment of Urology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China;
| | - Chuan-Xi Huang
- College of Life ScienceHebei UniversityHebeiChinaCollege of Life Science, Hebei University, Hebei, China;
| | - Shi-Kui Wu
- Department of Urologythe Fifth Medical CenterChinese PLA General HospitalBeijingChinaDepartment of Urology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China;
| | - Lan Yu
- Laboratory of Medical Molecular BiologyBeijing Institute of BiotechnologyBeijingChinaLaboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Guang-Jian Zhou
- Laboratory of Medical Molecular BiologyBeijing Institute of BiotechnologyBeijingChinaLaboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Li-Jun Chen
- Department of Urologythe Fifth Medical CenterChinese PLA General HospitalBeijingChinaDepartment of Urology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China;
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16
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Malipatil NS, Yadegarfar G, Lunt M, Keevil B, Siddals K, Livingston M, Roberts S, Narayanan P, Rutter M, Gibson JM, Donn R, Hackett G, Jones TH, Heald A. Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes. Endocrinol Diabetes Metab 2019; 2:e00064. [PMID: 31294081 PMCID: PMC6613223 DOI: 10.1002/edm2.64] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 02/01/2019] [Accepted: 02/02/2019] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Hypogonadism is more prevalent in men with type 2 diabetes (T2DM) (25%-40%) than in men without T2DM. Hypogonadism has been associated with poorer glycaemic outcomes and increased cardiovascular morbidity/mortality. We report a 14-year follow-up study to evaluate the influence of baseline testosterone level on T2DM outcomes. RESEARCH DESIGN AND METHODS A total of 550 men with T2DM underwent baseline total testosterone and dihydrotestosterone measurement by tandem mass spectrometry. Mean age of the men was 59.7 ± 12 (mean ± SD) years. Sex hormone-binding globulin (SHBG) was measured and free testosterone estimated. Patients were followed up between 2002 and 2016. Mean follow-up period was 12.2 ± 4 years using the Salford (UK) Integrated Health Records system. RESULTS Mean baseline total testosterone was 13.7 ± 5.8 nmol/L, and mean free testosterone was 245.7 ± 88.0 pmol/L. Mean for low total testosterone (<10 nmol/L) was 7.6 ± 2.0 nmol/L (n = 154) and 142 men had a free testosterone <190 pmol/L. During the 14-year duration follow-up, 22% of men experienced a myocardial infarction, 18% experienced a stroke, 11% developed angina, 14% underwent coronary revascularization. About 38% of the men initially recruited died. A lower total testosterone was associated with a higher body mass index (kg/m2) at follow-up: regression coefficient -0.30 (95% CI -0.445 to -0.157), P = 0.0001. The mortality rate was higher in patients with lower total testosterone compared to normal baseline total testosterone (5.0% vs 2.8% per year, P < 0.0001). A similar phenomenon was seen for dihydrotestosterone (4.3% vs 2.9% per year, P = 0.002) for normal vs low dihydrotestosterone) and for lower SHBG. Over the whole follow-up period 36.1% (143/396), men with normal baseline testosterone died vs 55.8% (86/154) of hypogonadal men at baseline. In Cox regression, the age-adjusted hazard ratio (HR) for higher mortality associated with low total testosterone was 1.54 (95% CI: 1.2-2.0, P < 0.002), corresponding to a 3.2 year reduced life expectancy for hypogonadal T2DM men. CONCLUSION Low testosterone and dihydrotestosterone levels are associated with higher all-cause mortality in T2DM men. Hypogonadal men with T2DM should be considered as very high risk for cardiovascular events/death.
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Affiliation(s)
- Nagaraj S. Malipatil
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
- Department of Diabetes and EndocrinologySalford Royal HospitalSalfordUK
| | - Ghasem Yadegarfar
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
- Heart Failure Research Centre (HF/PROVE), School of Public HealthIsfahan University of Medical SciencesIsfahanIran
| | - Mark Lunt
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
| | - Brian Keevil
- University of South Manchester NHS Foundation TrustManchesterUK
| | - Kirk Siddals
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
| | | | - Siriol Roberts
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
| | - Prakash Narayanan
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
| | - Martin Rutter
- Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Manchester University NHS Foundation TrustManchesterUK
| | - J. Martin Gibson
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
- Department of Diabetes and EndocrinologySalford Royal HospitalSalfordUK
| | - Rachelle Donn
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
| | - Geoff Hackett
- Department of Sexual MedicineHeartlands HospitalBirminghamUK
| | - T. Hugh Jones
- Department of Oncology and MetabolismUniversity of SheffieldSheffieldUK
| | - Adrian Heald
- The School of Medicine and Manchester Academic Health Sciences CentreUniversity of ManchesterManchesterUK
- Department of Diabetes and EndocrinologySalford Royal HospitalSalfordUK
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17
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Fararjeh AS, Liu YN. ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer. Int J Mol Sci 2019; 20:E2802. [PMID: 31181727 PMCID: PMC6600524 DOI: 10.3390/ijms20112802] [Citation(s) in RCA: 12] [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: 03/19/2019] [Revised: 05/25/2019] [Accepted: 06/04/2019] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PCa) is the second most common killer among men in Western countries. Targeting androgen receptor (AR) signaling by androgen deprivation therapy (ADT) is the current therapeutic regime for patients newly diagnosed with metastatic PCa. However, most patients relapse and become resistant to ADT, leading to metastatic castration-resistant PCa (CRPC) and eventually death. Several proposed mechanisms have been proposed for CRPC; however, the exact mechanism through which CRPC develops is still unclear. One possible pathway is that the AR remains active in CRPC cases. Therefore, understanding AR signaling networks as primary PCa changes into metastatic CRPC is key to developing future biomarkers and therapeutic strategies for PCa and CRPC. In the current review, we focused on three novel biomarkers (ZBTB46, SPDEF, and ETV6) that were demonstrated to play critical roles in CRPC progression, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) drug resistance, and the epithelial-to-mesenchymal transition (EMT) for patients treated with ADT or AR inhibition. In addition, we summarize how these potential biomarkers can be used in the clinic for diagnosis and as therapeutic targets of PCa.
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Affiliation(s)
- AbdulFattah Salah Fararjeh
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
| | - Yen-Nien Liu
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
- Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
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18
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Wackerhage H, Schoenfeld BJ, Hamilton DL, Lehti M, Hulmi JJ. Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise. J Appl Physiol (1985) 2018; 126:30-43. [PMID: 30335577 DOI: 10.1152/japplphysiol.00685.2018] [Citation(s) in RCA: 188] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
One of the most striking adaptations to exercise is the skeletal muscle hypertrophy that occurs in response to resistance exercise. A large body of work shows that a mammalian target of rapamycin complex 1 (mTORC1)-mediated increase of muscle protein synthesis is the key, but not sole, mechanism by which resistance exercise causes muscle hypertrophy. While much of the hypertrophy signaling cascade has been identified, the initiating, resistance exercise-induced and hypertrophy-stimulating stimuli have remained elusive. For the purpose of this review, we define an initiating, resistance exercise-induced and hypertrophy-stimulating signal as "hypertrophy stimulus," and the sensor of such a signal as "hypertrophy sensor." In this review we discuss our current knowledge of specific mechanical stimuli, damage/injury-associated and metabolic stress-associated triggers, as potential hypertrophy stimuli. Mechanical signals are the prime hypertrophy stimuli candidates, and a filamin-C-BAG3-dependent regulation of mTORC1, Hippo, and autophagy signaling is a plausible albeit still incompletely characterized hypertrophy sensor. Other candidate mechanosensing mechanisms are nuclear deformation-initiated signaling or several mechanisms related to costameres, which are the functional equivalents of focal adhesions in other cells. While exercise-induced muscle damage is probably not essential for hypertrophy, it is still unclear whether and how such muscle damage could augment a hypertrophic response. Interventions that combine blood flow restriction and especially low load resistance exercise suggest that resistance exercise-regulated metabolites could be hypertrophy stimuli, but this is based on indirect evidence and metabolite candidates are poorly characterized.
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Affiliation(s)
- Henning Wackerhage
- Department of Sport and Exercise Sciences, Technical University of Munich , Munich , Germany
| | | | - D Lee Hamilton
- Faculty of Health, School of Exercise and Nutrition Sciences, Deakin University , Victoria , Australia
| | - Maarit Lehti
- LIKES Research Centre for Physical Activity and Health , Jyväskylä , Finland
| | - Juha J Hulmi
- Neuromuscular Research Center, Biology of Physical Activity, Faculty of Sport and Health Sciences, University of Jyväskylä , Jyväskylä , Finland
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19
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Mechanism underlying the retarded nuclear translocation of androgen receptor splice variants. SCIENCE CHINA-LIFE SCIENCES 2018; 62:257-267. [PMID: 30267260 DOI: 10.1007/s11427-018-9379-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 08/14/2018] [Indexed: 12/25/2022]
Abstract
As shown in our previous study, two alternatively spliced androgen receptor (AR) variants, which are exclusively expressed in the granulosa cells of patients with polycystic ovary syndrome, exhibit retarded nuclear translocation compared with wild-type AR. However, researchers have not yet determined whether these abnormalities correlate with heat shock protein 90 (HSP90) and importin α (the former is a generally accepted co-chaperone of AR, and the latter is a component of classical nuclear import complexes). Here, these two variants were mainly retained in cytoplasm with HSP90 and importin α in the presence of dihydrotestosterone (DHT), and their levels in nucleus were significantly reduced, according to the immunofluorescence staining. The binding affinity of two AR variants for importin α was consistently decreased, while it was increased in WT-AR following DHT stimulation, leading to reduced nuclear import, particularly for the insertion-AR (Ins-AR). However, the binding affinities of two AR variants for HSP90 were increased in the absence of DHT compared with WT-AR, which functioned to maintain spatial structural stability, particularly for the deletion-AR (Del-AR). Therefore, the retarded nuclear translocation of two AR variants is associated with HSP90 and importin α, and the abnormal binding affinities for them play critical roles in this process.
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Gubbels Bupp MR, Jorgensen TN. Androgen-Induced Immunosuppression. Front Immunol 2018; 9:794. [PMID: 29755457 PMCID: PMC5932344 DOI: 10.3389/fimmu.2018.00794] [Citation(s) in RCA: 239] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 04/03/2018] [Indexed: 12/17/2022] Open
Abstract
In addition to determining biological sex, sex hormones are known to influence health and disease via regulation of immune cell activities and modulation of target-organ susceptibility to immune-mediated damage. Systemic autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis are more prevalent in females, while cancer shows the opposite pattern. Sex hormones have been repeatedly suggested to play a part in these biases. In this review, we will discuss how androgens and the expression of functional androgen receptor affect immune cells and how this may dampen or alter immune response(s) and affect autoimmune disease incidences and progression.
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Affiliation(s)
| | - Trine N Jorgensen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
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21
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Signaling regulation and role of filamin A cleavage in Ca2+-stimulated migration of androgen receptor-deficient prostate cancer cells. Oncotarget 2018; 8:3840-3853. [PMID: 27206800 PMCID: PMC5354799 DOI: 10.18632/oncotarget.9472] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 04/24/2016] [Indexed: 01/05/2023] Open
Abstract
Ca2+, a ubiquitous cellular signal, and filamin A, an actin-binding protein, play an important role in the regulation of cell adhesion, shape and motility. Using transwell filters to analyze cell migration, we found that extracellular Ca2+ (Cao2+) promotes the migration of androgen receptor (AR)-deficient and highly metastatic prostate cancer cell lines (DU145 and PC-3) compared to AR-positive and relatively less metastatic prostate cancer cells (LNCaP). Furthermore, we found that expression of filamin A is up-regulated in DU145 and PC-3 cells, and that Cao2+ significantly induces the cleavage of filamin A. Silencing expression of Ca2+-sensing receptor (CaR) and p115RhoGEF, and treating with leupeptin, a protease inhibitor, and ALLM, a calpain specific inhibitor, we further demonstrate that Cao2+-induced filamin A cleavage occurs via a CaR- p115RhoGEF-calpain dependent pathway. Our data show that Cao2+ via CaR- mediated signaling induces filamin A cleavage and promotes the migration in AR-deficient and highly metastatic prostate cancer cells.
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Zhang Y, Zhu T, Liu J, Liu J, Gao D, Su T, Zhao R. FLNa negatively regulated proliferation and metastasis in lung adenocarcinoma A549 cells via suppression of EGFR. Acta Biochim Biophys Sin (Shanghai) 2018; 50:164-170. [PMID: 29272322 DOI: 10.1093/abbs/gmx135] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Indexed: 01/30/2023] Open
Abstract
Filamin A (FLNa) is a ubiquitously expressed cytoplasmic protein, which composes of an N-terminal actin binding domain (ABD) followed by 24 Ig-like repeats. FLNa functions as a cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and serves as a signaling intermediate. Recent studies have identified FLNa as a scaffold protein that interacts with over 90 proteins and plays vital roles in cellular signaling transduction. Mutations or defects in human FLNa gene have been shown to cause numerous developmental defects. Moreover, aberrant expression of FLNa has been observed in many cancers, such as parathyroid tumor, cervical cancer, and breast cancer. However, its role in lung adenocarcinoma has seldom been discussed. In the present study, our in vitro and in vivo studies demonstrated that silencing FLNa expression in lung cancer cell line A549 cells promoted proliferation, migration, and invasiveness of A549 cells by enhancing the activation of epidermal growth factor receptor and ERK signaling pathway. These results shed light on novel functions of FLNa in lung cancer and uncovered novel mechanisms, these results provided possible targets for the prediction and treatment for lung adenocarcinoma.
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Affiliation(s)
- Yuna Zhang
- Department of Endocrinology, Fourth Hospital, Hebei Medical University, Shijiazhuang 050011, China
| | - Tienian Zhu
- Department of Immunology, Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Hebei Medical University, Shijiazhuang 050017, China
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China
| | - Jingpu Liu
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China
| | - Jiankun Liu
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China
| | - Dongmei Gao
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China
| | - Tongyi Su
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, China
| | - Ruijing Zhao
- Department of Immunology, Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Hebei Medical University, Shijiazhuang 050017, China
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Abstract
The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, progression to castration-resistant prostate cancer (CRPC) typically follows and is largely the result of restored androgen signaling. Efforts to understand the mechanisms behind CRPC have revealed new insights into dysregulated androgen signaling and intratumoral androgen synthesis, which has ultimately led to the development of several novel androgen receptor (AR)-directed therapies for CRPC. However, emergence of resistance to these newer agents has also galvanized new directions in investigations of prereceptor and postreceptor AR regulation. Here, we review our current understanding of AR signaling as it pertains to the biology and natural history of prostate cancer.
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Affiliation(s)
- Charles Dai
- Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195
| | - Hannelore Heemers
- Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195
- Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195
- Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195
| | - Nima Sharifi
- Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195
- Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195
- Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195
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Presence of Androgen Receptor Variant in Neuronal Lipid Rafts. eNeuro 2017; 4:eN-NWR-0109-17. [PMID: 28856243 PMCID: PMC5575139 DOI: 10.1523/eneuro.0109-17.2017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 08/03/2017] [Accepted: 08/14/2017] [Indexed: 11/21/2022] Open
Abstract
Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane–initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats. This putative splice variant protein has a molecular weight of 45 kDa and lacks an N-terminal domain, indicating it is homologous to the human AR45 splice variant. Interestingly, AR45 was highly expressed in all brain regions examined. In dopaminergic neurons, AR45 is localized to plasma membrane lipid rafts, a microdomain involved in cellular signaling. Further, AR45 protein interacts with membrane-associated G proteins Gαq and Gαo. Neither age nor hormone levels altered AR45 expression in dopaminergic neurons. These results provide the first evidence of AR45 protein expression in the brain, specifically plasma membrane lipid rafts. AR45 presence in lipid rafts indicates that it may function as a membrane androgen receptor to mediate fast, nongenomic androgen actions.
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Martínez-Rivera FJ, Pérez-Laspiur J, Santiago-Gascot ME, Alemán-Reyes AG, García-Santiago E, Rodríguez-Pérez Y, Calo-Guadalupe C, Otero-Pagán I, Ayala-Pagán RN, Martínez M, Cantres-Rosario YM, Meléndez LM, Barreto-Estrada JL. Differential protein expression profile in the hypothalamic GT1-7 cell line after exposure to anabolic androgenic steroids. PLoS One 2017; 12:e0180409. [PMID: 28719635 PMCID: PMC5515402 DOI: 10.1371/journal.pone.0180409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 06/15/2017] [Indexed: 11/19/2022] Open
Abstract
The abuse of anabolic androgenic steroids (AAS) has been considered a major public health problem during decades. Supraphysiological doses of AAS may lead to a variety of neuroendocrine problems. Precisely, the hypothalamic-pituitary-gonadal (HPG) axis is one of the body systems that is mainly influenced by steroidal hormones. Fluctuations of the hormonal milieu result in alterations of reproductive function, which are made through changes in hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH). In fact, previous studies have shown that AAS modulate the activity of these neurons through steroid-sensitive afferents. To increase knowledge about the cellular mechanisms induced by AAS in GnRH neurons, we performed proteomic analyses of the murine hypothalamic GT1-7 cell line after exposure to 17α-methyltestosterone (17α-meT; 1 μM). These cells represent a good model for studying regulatory processes because they exhibit the typical characteristics of GnRH neurons, and respond to compounds that modulate GnRH in vivo. Two-dimensional difference in gel electrophoresis (2D-DIGE) and mass spectrometry analyses identified a total of 17 different proteins that were significantly affected by supraphysiological levels of AAS. Furthermore, pathway analyses showed that modulated proteins were mainly associated to glucose metabolism, drug detoxification, stress response and cell cycle. Validation of many of these proteins, such as GSTM1, ERH, GAPDH, PEBP1 and PDIA6, were confirmed by western blotting. We further demonstrated that AAS exposure decreased expression of estrogen receptors and GnRH, while two important signaling pathway proteins p-ERK, and p-p38, were modulated. Our results suggest that steroids have the capacity to directly affect the neuroendocrine system by modulating key cellular processes for the control of reproductive function.
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Affiliation(s)
- Freddyson J. Martínez-Rivera
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Juliana Pérez-Laspiur
- Translational Proteomics Center-RCMI, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - María E. Santiago-Gascot
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Abner G. Alemán-Reyes
- Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico, United States of America
| | - Emanuel García-Santiago
- Department of Biotechnology, Universidad del Este, Carolina, Puerto Rico, United States of America
| | - Yolanda Rodríguez-Pérez
- Translational Proteomics Center-RCMI, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Cristhian Calo-Guadalupe
- Department of Biotechnology, Universidad del Este, Carolina, Puerto Rico, United States of America
| | - Inelia Otero-Pagán
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Roxsana N. Ayala-Pagán
- Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico, United States of America
| | - Magdiel Martínez
- Department of Physiology and Biophysics, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Yisel M. Cantres-Rosario
- Department of Microbiology and Medical Zoology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Loyda M. Meléndez
- Translational Proteomics Center-RCMI, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
- Department of Microbiology and Medical Zoology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
| | - Jennifer L. Barreto-Estrada
- Department of Anatomy and Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico, United States of America
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Carrera-García L, Rivas-Crespo MF, Fernández García MS. Androgen receptor dysfunction as a prevalent manifestation in young male carriers of a FLNA gene mutation. Am J Med Genet A 2017; 173:1710-1713. [PMID: 28432720 DOI: 10.1002/ajmg.a.38230] [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: 08/09/2016] [Accepted: 03/01/2017] [Indexed: 01/23/2023]
Abstract
Androgenic actions require the proper signal transmission by the androgen receptor (AR), a nuclear transcription factor. This is initially located in the cell cytoplasm and should translocates to the nucleus to interact with DNA. AR functional impairment causes diverse blockage degrees of androgenic steroid action, known as androgen insensitivity syndromes. Filamin A, a protein coded by the FLNA gene, is a co-activator of various cytoplasmic factors, including AR. The mutational inactivation of the FLNA gene induces insufficiency of translocation and activation of AR. Consequently, it causes a developmental disorder of the male gonad and hypogonadism, similar to those observed in partial androgen insensitivity. We report two brothers carrying a loss-of-function mutation of FNLA with gonadal differentiation disorder and hypospadias. Specific staining for AR shows almost an absolute absence of these receptors in the testicular tissue. This association recommends investigating a possible mutational inactivation of the FLNA gene in patients with cryptorchidism and epididymo-testicular dissociation. The study is especially indicated when the family history, more often that of the mother, is suggestive. Likewise, growth and gonadal development of all male patients carrying this genetic trait should be monitored since childhood.
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Affiliation(s)
- Laura Carrera-García
- Pediatric Neurology, Hospital Universitario Central de Asturias, University of Oviedo, Oviedo, Spain
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Leung JK, Sadar MD. Non-Genomic Actions of the Androgen Receptor in Prostate Cancer. Front Endocrinol (Lausanne) 2017; 8:2. [PMID: 28144231 PMCID: PMC5239799 DOI: 10.3389/fendo.2017.00002] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 01/05/2017] [Indexed: 12/15/2022] Open
Abstract
Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens. In the canonical pathway, binding of androgen to AR LBD triggers the release of AR from molecular chaperones which enable conformational changes and protein-protein interactions to facilitate its nuclear translocation where it regulates the expression of target genes. However, preceding AR function in the nucleus, initial binding of androgen to AR LBD in the cytoplasm may already initiate signal transduction pathways to modulate cellular proliferation and migration. In this article, we review the significance of signal transduction pathways activated by rapid, non-genomic signaling of the AR during the progression to metastatic CRPC and put into perspective the implications for current and novel therapies that target different domains of AR.
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Affiliation(s)
- Jacky K. Leung
- Department of Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Marianne D. Sadar
- Department of Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
- *Correspondence: Marianne D. Sadar,
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Castoria G, Auricchio F, Migliaccio A. Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis. FASEB J 2016; 31:1289-1300. [PMID: 28031322 DOI: 10.1096/fj.201601047r] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 12/19/2016] [Indexed: 01/11/2023]
Abstract
In this review, we focus on the role played by the protein partners of ligand-activated extranuclear androgen receptor (AR) in the final effects of hormone action, such as proliferation, migration, and neuritogenesis. The choice of AR partner, at least in part, depends on cell type. Androgen-activated receptor directly associates with cytoplasmic Src tyrosine kinase in epithelial cells, whereas in mesenchymal and neuronal cells, it prevalently interacts with filamin A. In the former, proliferation represents the final hormonal outcome, whereas in the latter, either migration or neuritogenesis, respectively, occurs. Furthermore, AR partner filamin A is replaced with Src when mesenchymal cells are stimulated with very low androgen concentrations. Consequently, the migratory effect is replaced by mitogenesis. Use of peptides that prevent receptor/partner assembly abolishes the effects that are dependent on their association and offers new therapeutic approaches to AR-related diseases. Perturbation of migration is often associated with metastatic spreading in cancer. In turn, cell cycle aberration causes tumors to grow faster, whereas toxic signaling triggers neurodegenerative events in the CNS. Here, we provide examples of new tools that interfere in rapid androgen effects, including migration, proliferation, and neuronal differentiation, together with their potential therapeutic applications in AR-dependent diseases-mainly prostate cancer and neurodegenerative disorders.-Castoria, G., Auricchio, F., Migliaccio, A. Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis.
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Affiliation(s)
- Gabriella Castoria
- Department of Biochemistry, Biophysics, and General Pathology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Ferdinando Auricchio
- Department of Biochemistry, Biophysics, and General Pathology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Antimo Migliaccio
- Department of Biochemistry, Biophysics, and General Pathology, University of Campania "Luigi Vanvitelli," Naples, Italy
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29
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Di Zazzo E, Galasso G, Giovannelli P, Di Donato M, Di Santi A, Cernera G, Rossi V, Abbondanza C, Moncharmont B, Sinisi AA, Castoria G, Migliaccio A. Prostate cancer stem cells: the role of androgen and estrogen receptors. Oncotarget 2016; 7:193-208. [PMID: 26506594 PMCID: PMC4807992 DOI: 10.18632/oncotarget.6220] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 09/30/2015] [Indexed: 12/22/2022] Open
Abstract
Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable. Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment. In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy.
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Affiliation(s)
- Erika Di Zazzo
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Giovanni Galasso
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Pia Giovannelli
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Marzia Di Donato
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Annalisa Di Santi
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Gustavo Cernera
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Valentina Rossi
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Ciro Abbondanza
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | | | - Antonio Agostino Sinisi
- Endocrinology Section, Department of Cardio-Thoracic and Respiratory Diseases, II University of Naples, Naples, Italy
| | - Gabriella Castoria
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Antimo Migliaccio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
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30
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Hsiao JJ, Smits MM, Ng BH, Lee J, Wright ME. Discovery Proteomics Identifies a Molecular Link between the Coatomer Protein Complex I and Androgen Receptor-dependent Transcription. J Biol Chem 2016; 291:18818-42. [PMID: 27365400 PMCID: PMC5009256 DOI: 10.1074/jbc.m116.732313] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Indexed: 12/18/2022] Open
Abstract
Aberrant androgen receptor (AR)-dependent transcription is a hallmark of human prostate cancers. At the molecular level, ligand-mediated AR activation is coordinated through spatial and temporal protein-protein interactions involving AR-interacting proteins, which we designate the “AR-interactome.” Despite many years of research, the ligand-sensitive protein complexes involved in ligand-mediated AR activation in prostate tumor cells have not been clearly defined. Here, we describe the development, characterization, and utilization of a novel human LNCaP prostate tumor cell line, N-AR, which stably expresses wild-type AR tagged at its N terminus with the streptavidin-binding peptide epitope (streptavidin-binding peptide-tagged wild-type androgen receptor; SBP-AR). A bioanalytical workflow involving streptavidin chromatography and label-free quantitative mass spectrometry was used to identify SBP-AR and associated ligand-sensitive cytosolic proteins/protein complexes linked to AR activation in prostate tumor cells. Functional studies verified that ligand-sensitive proteins identified in the proteomic screen encoded modulators of AR-mediated transcription, suggesting that these novel proteins were putative SBP-AR-interacting proteins in N-AR cells. This was supported by biochemical associations between recombinant SBP-AR and the ligand-sensitive coatomer protein complex I (COPI) retrograde trafficking complex in vitro. Extensive biochemical and molecular experiments showed that the COPI retrograde complex regulates ligand-mediated AR transcriptional activation, which correlated with the mobilization of the Golgi-localized ARA160 coactivator to the nuclear compartment of prostate tumor cells. Collectively, this study provides a bioanalytical strategy to validate the AR-interactome and define novel AR-interacting proteins involved in ligand-mediated AR activation in prostate tumor cells. Moreover, we describe a cellular system to study how compartment-specific AR-interacting proteins influence AR activation and contribute to aberrant AR-dependent transcription that underlies the majority of human prostate cancers.
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Affiliation(s)
- Jordy J Hsiao
- From the Department of Molecular Physiology and Biophysics, Carver College of Medicine, Iowa City, Iowa 52242
| | - Melinda M Smits
- From the Department of Molecular Physiology and Biophysics, Carver College of Medicine, Iowa City, Iowa 52242
| | - Brandon H Ng
- From the Department of Molecular Physiology and Biophysics, Carver College of Medicine, Iowa City, Iowa 52242
| | - Jinhee Lee
- From the Department of Molecular Physiology and Biophysics, Carver College of Medicine, Iowa City, Iowa 52242
| | - Michael E Wright
- From the Department of Molecular Physiology and Biophysics, Carver College of Medicine, Iowa City, Iowa 52242
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31
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Zheng M, Zhang X, Sun N, Min C, Zhang X, Kim KM. RalA employs GRK2 and β-arrestins for the filamin A-mediated regulation of trafficking and signaling of dopamine D2 and D3 receptor. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:2072-83. [PMID: 27188791 DOI: 10.1016/j.bbamcr.2016.05.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/10/2016] [Accepted: 05/13/2016] [Indexed: 12/13/2022]
Abstract
Filamin A (FLNA) is known to act as platform for the signaling and intracellular trafficking of various GPCRs including dopamine D2 and D3 receptors (D2R, D3R). To understand molecular mechanisms involved in the FLNA-mediated regulation of D2R and D3R, comparative studies were conducted on the signaling and intracellular trafficking of the D2R and D3R in FLNA-knockdown cells, with a specific focus on the roles of the proteins that interact with FLNA and the D2R and D3R. Lowering the level of cellular FLNA caused an elevation in RalA activity and resulted in selective interference with the normal intracellular trafficking and signaling of the D2R and D3R, through GRK2 and β-arrestins, respectively. Knockdown of FLNA or coexpression of active RalA interfered with the recycling of the internalized D2R and resulted in the development of receptor tolerance. Active RalA was found to interact with GRK2 to sequester it from D2R. Knockdown of FLNA or coexpression of active RalA prevented D3R from coupling with G protein. The selective involvement of GRK2- and β-arrestins in the RalA-mediated cellular processes of the D2R and D3R was achieved via their different modes of interactions with the receptor and their distinct functional roles in receptor regulation. Our results show that FLNA is a multi-functional protein that acts as a platform on which D2R and D3R can interact with various proteins, through which selective regulation of these receptors occurs in combination with GRK2 and β-arrestins.
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Affiliation(s)
- Mei Zheng
- Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju 500-757, Republic of Korea
| | - Xiaohan Zhang
- Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju 500-757, Republic of Korea
| | - NingNing Sun
- Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju 500-757, Republic of Korea
| | - Chengchun Min
- Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju 500-757, Republic of Korea
| | - Xiaowei Zhang
- Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju 500-757, Republic of Korea
| | - Kyeong-Man Kim
- Department of Pharmacology, College of Pharmacy, Drug Development Research Institute, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
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Liao RS, Ma S, Miao L, Li R, Yin Y, Raj GV. Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation. Transl Androl Urol 2016; 2:187-96. [PMID: 26816736 PMCID: PMC4708176 DOI: 10.3978/j.issn.2223-4683.2013.09.07] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Androgen receptor (AR)-mediated signaling is necessary for prostate cancer cell proliferation and an important target for therapeutic drug development. Canonically, AR signals through a genomic or transcriptional pathway, involving the translocation of androgen-bound AR to the nucleus, its binding to cognate androgen response elements on promoter, with ensuing modulation of target gene expression, leading to cell proliferation. However, prostate cancer cells can show dose-dependent proliferation responses to androgen within minutes, without the need for genomic AR signaling. This proliferation response known as the non-genomic AR signaling is mediated by cytoplasmic AR, which facilitates the activation of kinase-signaling cascades, including the Ras-Raf-1, phosphatidyl-inositol 3-kinase (PI3K)/Akt and protein kinase C (PKC), which in turn converge on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation, leading to cell proliferation. Further, since activated ERK may also phosphorylate AR and its coactivators, the non-genomic AR signaling may enhance AR genomic activity. Non-genomic AR signaling may occur in an ERK-independent manner, via activation of mammalian target of rapamycin (mTOR) pathway, or modulation of intracellular Ca2+ concentration through plasma membrane G protein-coupled receptors (GPCRs). These data suggest that therapeutic strategies aimed at preventing AR nuclear translocation and genomic AR signaling alone may not completely abrogate AR signaling. Thus, elucidation of mechanisms that underlie non-genomic AR signaling may identify potential mechanisms of resistance to current anti-androgens and help developing novel therapies that abolish all AR signaling in prostate cancer.
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Affiliation(s)
- Ross S Liao
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
| | - Shihong Ma
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
| | - Lu Miao
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
| | - Rui Li
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
| | - Yi Yin
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
| | - Ganesh V Raj
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
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Kircher P, Hermanns C, Nossek M, Drexler MK, Grosse R, Fischer M, Sarikas A, Penkava J, Lewis T, Prywes R, Gudermann T, Muehlich S. Filamin A interacts with the coactivator MKL1 to promote the activity of the transcription factor SRF and cell migration. Sci Signal 2015; 8:ra112. [PMID: 26554816 DOI: 10.1126/scisignal.aad2959] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Megakaryoblastic leukemia 1 (MKL1) is a coactivator of serum response factor (SRF) that promotes the expression of genes associated with cell proliferation, motility, adhesion, and differentiation-processes that also involve dynamic cytoskeletal changes in the cell. MKL1 is inactive when bound to monomeric globular actin (G-actin), but signals that activate the small guanosine triphosphatase RhoA cause actin polymerization and MKL1 dissociation from G-actin. We found a new mechanism of MKL1 activation that is mediated through its binding to filamin A (FLNA), a protein that binds filamentous actin (F-actin). The interaction of FLNA and MKL1 was required for the expression of MKL1 target genes in primary fibroblasts, melanoma, mammary and hepatocellular carcinoma cells. We identified the regions of interaction between MKL1 and FLNA, and cells expressing an MKL1 mutant that was unable to bind FLNA exhibited impaired cell migration and reduced expression of MKL1-SRF target genes. Induction and repression of MKL1-SRF target genes correlated with increased or decreased MKL1-FLNA interaction, respectively. Lysophosphatidic acid-induced RhoA activation in primary human fibroblasts promoted the association of endogenous MKL1 with FLNA, whereas exposure to an actin polymerization inhibitor dissociated MKL1 from FLNA and decreased MKL1-SRF target gene expression in melanoma cells. Thus, FLNA functions as a positive cellular transducer linking actin polymerization to MKL1-SRF activity, counteracting the known repressive complex of MKL1 and monomeric G-actin.
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Affiliation(s)
- Philipp Kircher
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany
| | - Constanze Hermanns
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany
| | - Maximilian Nossek
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany
| | - Maria Katharina Drexler
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany
| | - Robert Grosse
- Institute of Pharmacology, Biochemical-Pharmacological Center, University of Marburg, Marburg 35043, Germany
| | - Maximilian Fischer
- Institute of Pharmacology and Toxicology, Technical University Munich, Munich 80802, Germany
| | - Antonio Sarikas
- Institute of Pharmacology and Toxicology, Technical University Munich, Munich 80802, Germany
| | - Josef Penkava
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany
| | - Thera Lewis
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Ron Prywes
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Thomas Gudermann
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany. Comprehensive Pneumology Center Munich, German Center for Lung Research, Munich 81377, Germany. German Center for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich 80802, Germany
| | - Susanne Muehlich
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany.
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Shao QQ, Zhang TP, Zhao WJ, Liu ZW, You L, Zhou L, Guo JC, Zhao YP. Filamin A: Insights into its Exact Role in Cancers. Pathol Oncol Res 2015; 22:245-52. [DOI: 10.1007/s12253-015-9980-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 09/01/2015] [Indexed: 11/29/2022]
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Di Donato M, Bilancio A, D'Amato L, Claudiani P, Oliviero MA, Barone MV, Auricchio A, Appella E, Migliaccio A, Auricchio F, Castoria G. Cross-talk between androgen receptor/filamin A and TrkA regulates neurite outgrowth in PC12 cells. Mol Biol Cell 2015; 26:2858-72. [PMID: 26063730 PMCID: PMC4571344 DOI: 10.1091/mbc.e14-09-1352] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 05/14/2015] [Accepted: 06/04/2015] [Indexed: 12/17/2022] Open
Abstract
Steroids and growth factors control neuronal development through their receptors under physiological and pathological conditions. We show that PC12 cells harbor endogenous androgen receptor (AR), whose inhibition or silencing strongly interferes with neuritogenesis stimulated by the nonaromatizable synthetic androgen R1881 or NGF. This implies a role for AR not only in androgen signaling, but also in NGF signaling. In turn, a pharmacological TrkA inhibitor interferes with NGF- or androgen-induced neuritogenesis. In addition, androgen or NGF triggers AR association with TrkA, TrkA interaction with PI3-K δ, and downstream activation of PI3-K δ and Rac in PC12 cells. Once associated with AR, filamin A (FlnA) contributes to androgen or NGF neuritogenesis, likely through its interaction with signaling effectors, such as Rac. This study thus identifies a previously unrecognized reciprocal cross-talk between AR and TrkA, which is controlled by β1 integrin. The contribution of FlnA/AR complex and PI3-K δ to neuronal differentiation by androgens and NGF is also novel. This is the first description of AR function in PC12 cells.
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Affiliation(s)
- Marzia Di Donato
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, 80138 Naples, Italy
| | - Antonio Bilancio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, 80138 Naples, Italy
| | - Loredana D'Amato
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, 80138 Naples, Italy
| | - Pamela Claudiani
- Telethon Institute of Genetics and Medicine and Medical Genetics and Translational Medicine Department, University Federico II, 80131 Naples, Italy
| | - Maria Antonietta Oliviero
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, 80138 Naples, Italy
| | - Maria Vittoria Barone
- European Laboratory for the Investigation of Food Induced Diseases and Medical Genetics and Translational Medicine Department, University Federico II, 80131 Naples, Italy
| | - Alberto Auricchio
- Telethon Institute of Genetics and Medicine and Medical Genetics and Translational Medicine Department, University Federico II, 80131 Naples, Italy
| | - Ettore Appella
- Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892-4256
| | - Antimo Migliaccio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, 80138 Naples, Italy
| | - Ferdinando Auricchio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, 80138 Naples, Italy
| | - Gabriella Castoria
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, 80138 Naples, Italy
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Lichner Z, Ding Q, Samaan S, Saleh C, Nasser A, Al-Haddad S, Samuel JN, Fleshner NE, Stephan C, Jung K, Yousef GM. miRNAs dysregulated in association with Gleason grade regulate extracellular matrix, cytoskeleton and androgen receptor pathways. J Pathol 2015; 237:226-37. [DOI: 10.1002/path.4568] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 05/14/2015] [Accepted: 05/23/2015] [Indexed: 01/06/2023]
Affiliation(s)
- Zsuzsanna Lichner
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
| | - Qiang Ding
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
| | - Sara Samaan
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
| | - Carol Saleh
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
| | - Aurfan Nasser
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
- Department of Laboratory Medicine and Pathobiology; University of Toronto; M5G 1L5 Canada
| | - Sahar Al-Haddad
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
- Department of Laboratory Medicine and Pathobiology; University of Toronto; M5G 1L5 Canada
| | - Joseph N Samuel
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
| | - Neil E Fleshner
- Department of Surgery; University Health Network; Toronto Canada
| | - Carsten Stephan
- Department of Urology; University Hospital Charité; D-10117 Berlin Germany
| | - Klaus Jung
- Department of Urology; University Hospital Charité; D-10117 Berlin Germany
| | - George M Yousef
- Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute; St. Michael's Hospital; Toronto Canada
- Department of Laboratory Medicine and Pathobiology; University of Toronto; M5G 1L5 Canada
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Hsiao JJ, Ng BH, Smits MM, Martinez HD, Jasavala RJ, Hinkson IV, Fermin D, Eng JK, Nesvizhskii AI, Wright ME. Research Resource: Androgen Receptor Activity Is Regulated Through the Mobilization of Cell Surface Receptor Networks. Mol Endocrinol 2015; 29:1195-218. [PMID: 26181434 DOI: 10.1210/me.2015-1021] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The aberrant expression of androgen receptor (AR)-dependent transcriptional programs is a defining pathology of the development and progression of prostate cancers. Transcriptional cofactors that bind AR are critical determinants of prostate tumorigenesis. To gain a deeper understanding of the proteins linked to AR-dependent gene transcription, we performed a DNA-affinity chromatography-based proteomic screen designed to identify proteins involved in AR-mediated gene transcription in prostate tumor cells. Functional experiments validated the coregulator roles of known AR-binding proteins in AR-mediated transcription in prostate tumor cells. More importantly, novel coregulatory functions were detected in components of well-established cell surface receptor-dependent signal transduction pathways. Further experimentation demonstrated that components of the TNF, TGF-β, IL receptor, and epidermal growth factor signaling pathways modulated AR-dependent gene transcription and androgen-dependent proliferation in prostate tumor cells. Collectively, our proteomic dataset demonstrates that the cell surface receptor- and AR-dependent pathways are highly integrated, and provides a molecular framework for understanding how disparate signal-transduction pathways can influence AR-dependent transcriptional programs linked to the development and progression of human prostate cancers.
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Affiliation(s)
- Jordy J Hsiao
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Brandon H Ng
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Melinda M Smits
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Harryl D Martinez
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Rohini J Jasavala
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Izumi V Hinkson
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Damian Fermin
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Jimmy K Eng
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Alexey I Nesvizhskii
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
| | - Michael E Wright
- Department of Molecular Physiology and Biophysics (J.J.H., B.H.N., M.M.S., H.D.M., M.E.W.), Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242; Department of Pharmacology (H.D.M., R.J.J., I.V.H., M.E.W.), School of Medicine and Genome Center, University of California, Davis, California 95616; Departments of Pathology and Computational Medicine and Bioinformatics (D.F., A.I.N.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Genome Sciences (J.K.E.), University of Washington, Seattle, Washington 98195
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Savoy RM, Chen L, Siddiqui S, Melgoza FU, Durbin-Johnson B, Drake C, Jathal MK, Bose S, Steele TM, Mooso BA, D'Abronzo LS, Fry WH, Carraway KL, Mudryj M, Ghosh PM. Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer. Endocr Relat Cancer 2015; 22:369-86. [PMID: 25759396 PMCID: PMC4433410 DOI: 10.1530/erc-15-0021] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/10/2015] [Indexed: 02/06/2023]
Abstract
Prostate cancer (PCa) progression is regulated by the androgen receptor (AR); however, patients undergoing androgen-deprivation therapy (ADT) for disseminated PCa eventually develop castration-resistant PCa (CRPC). Results of previous studies indicated that AR, a transcription factor, occupies distinct genomic loci in CRPC compared with hormone-naïve PCa; however, the cause of this distinction was unknown. The E3 ubiquitin ligase Nrdp1 is a model AR target modulated by androgens in hormone-naïve PCa but not in CRPC. Using Nrdp1, we investigated how AR switches transcription programs during CRPC progression. The proximal Nrdp1 promoter contains an androgen response element (ARE); we demonstrated AR binding to this ARE in androgen-sensitive PCa. Analysis of hormone-naive human prostatectomy specimens revealed correlation between Nrdp1 and AR expression, supporting AR regulation of NRDP1 levels in androgen-sensitive tissue. However, despite sustained AR levels, AR binding to the Nrdp1 promoter and Nrdp1 expression were suppressed in CRPC. Elucidation of the suppression mechanism demonstrated correlation of NRDP1 levels with nuclear localization of the scaffolding protein filamin A (FLNA) which, as we previously showed, is itself repressed following ADT in many CRPC tumors. Restoration of nuclear FLNA in CRPC stimulated AR binding to Nrdp1 ARE, increased its transcription, and augmented NRDP1 protein expression and responsiveness to ADT, indicating that nuclear FLNA controls AR-mediated androgen-sensitive Nrdp1 transcription. Expression of other AR-regulated genes lost in CRPC was also re-established by nuclear FLNA. Thus, our results indicate that nuclear FLNA promotes androgen-dependent AR-regulated transcription in PCa, while loss of nuclear FLNA in CRPC alters the AR-regulated transcription program.
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Affiliation(s)
- Rosalinda M Savoy
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Liqun Chen
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Salma Siddiqui
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Frank U Melgoza
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Blythe Durbin-Johnson
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Christiana Drake
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Maitreyee K Jathal
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Swagata Bose
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Thomas M Steele
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Benjamin A Mooso
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Leandro S D'Abronzo
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - William H Fry
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Kermit L Carraway
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Maria Mudryj
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
| | - Paramita M Ghosh
- VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA
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Sukocheva OA, Li B, Due SL, Hussey DJ, Watson DI. Androgens and esophageal cancer: What do we know? World J Gastroenterol 2015; 21:6146-6156. [PMID: 26034350 PMCID: PMC4445092 DOI: 10.3748/wjg.v21.i20.6146] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 03/27/2015] [Accepted: 04/16/2015] [Indexed: 02/06/2023] Open
Abstract
Significant disparities exist between genders for the development and progression of several gastro-intestinal (GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors (AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome - poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer.
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41
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Mardilovich K, Gabrielsen M, McGarry L, Orange C, Patel R, Shanks E, Edwards J, Olson MF. Elevated LIM kinase 1 in nonmetastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation. Mol Cancer Ther 2015; 14:246-58. [PMID: 25344584 PMCID: PMC4297197 DOI: 10.1158/1535-7163.mct-14-0447] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Prostate cancer affects a large proportion of the male population, and is primarily driven by androgen receptor (AR) activity. First-line treatment typically consists of reducing AR signaling by hormone depletion, but resistance inevitably develops over time. One way to overcome this issue is to block AR function via alternative means, preferably by inhibiting protein targets that are more active in tumors than in normal tissue. By staining prostate cancer tumor sections, elevated LIM kinase 1 (LIMK1) expression and increased phosphorylation of its substrate Cofilin were found to be associated with poor outcome and reduced survival in patients with nonmetastatic prostate cancer. A LIMK-selective small molecule inhibitor (LIMKi) was used to determine whether targeted LIMK inhibition was a potential prostate cancer therapy. LIMKi reduced prostate cancer cell motility, as well as inhibiting proliferation and increasing apoptosis in androgen-dependent prostate cancer cells more effectively than in androgen-independent prostate cancer cells. LIMK inhibition blocked ligand-induced AR nuclear translocation, reduced AR protein stability and transcriptional activity, consistent with its effects on proliferation and survival acting via inhibition of AR activity. Furthermore, inhibition of LIMK activity increased αTubulin acetylation and decreased AR interactions with αTubulin, indicating that the role of LIMK in regulating microtubule dynamics contributes to AR function. These results indicate that LIMK inhibitors could be beneficial for the treatment of prostate cancer both by reducing nuclear AR translocation, leading to reduced proliferation and survival, and by inhibiting prostate cancer cell dissemination.
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Affiliation(s)
| | - Mads Gabrielsen
- Beatson Institute for Cancer Research, Glasgow, United Kingdom
| | - Lynn McGarry
- Beatson Institute for Cancer Research, Glasgow, United Kingdom
| | - Clare Orange
- Pathology Department, Division of Cancer Sciences and Molecular Pathology, Western Infirmary, University of Glasgow, Glasgow, United Kingdom
| | - Rachana Patel
- Beatson Institute for Cancer Research, Glasgow, United Kingdom
| | - Emma Shanks
- Beatson Institute for Cancer Research, Glasgow, United Kingdom
| | - Joanne Edwards
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Michael F Olson
- Beatson Institute for Cancer Research, Glasgow, United Kingdom.
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42
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Wang X, Li S. Protein mislocalization: mechanisms, functions and clinical applications in cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1846:13-25. [PMID: 24709009 PMCID: PMC4141035 DOI: 10.1016/j.bbcan.2014.03.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 02/20/2014] [Accepted: 03/27/2014] [Indexed: 12/21/2022]
Abstract
The changes from normal cells to cancer cells are primarily regulated by genome instability, which foster hallmark functions of cancer through multiple mechanisms including protein mislocalization. Mislocalization of these proteins, including oncoproteins, tumor suppressors, and other cancer-related proteins, can interfere with normal cellular function and cooperatively drive tumor development and metastasis. This review describes the cancer-related effects of protein subcellular mislocalization, the related mislocalization mechanisms, and the potential application of this knowledge to cancer diagnosis, prognosis, and therapy.
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Affiliation(s)
- Xiaohong Wang
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Shulin Li
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
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43
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Leach DA, Need EF, Trotta AP, Grubisha MJ, DeFranco DB, Buchanan G. Hic-5 influences genomic and non-genomic actions of the androgen receptor in prostate myofibroblasts. Mol Cell Endocrinol 2014; 384:185-99. [PMID: 24440747 DOI: 10.1016/j.mce.2014.01.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 12/27/2013] [Accepted: 01/03/2014] [Indexed: 01/31/2023]
Abstract
There is extensive knowledge of androgen receptor (AR) signaling in cancer cells, but less regarding androgen action in stromal cells of the tumor microenvironment. We report here the genome-wide effects of a stromal cell specific molecular adapter and AR coregulator, hydrogen peroxide-inducible gene 5 (Hic-5/TGFB1I1), on AR function in prostate myofibroblasts. Following androgen stimulation, Hic-5 rapidly translocates to the nucleus, coincident with increased phosphorylation of focal adhesion kinase. As a coregulator, Hic-5 acted to amplify or inhibit regulation of approximately 50% of AR target genes, affected androgen regulation of growth, cell adhesion, motility and invasion. These data suggest Hic-5 as a transferable adaptor between focal adhesions and the nucleus of prostate myofibroblasts, where it acts a key mediator of the specificity and sensitivity of AR signaling. We propose a model in which Hic-5 coordinates AR signaling with adhesion and extracellular matrix contacts to regulate cell behavior in the tumor microenvironment.
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Affiliation(s)
- Damien A Leach
- Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia
| | - Eleanor F Need
- Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia
| | - Andrew P Trotta
- Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia
| | - Melanie J Grubisha
- School of Medicine, Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA
| | - Donald B DeFranco
- School of Medicine, Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA
| | - Grant Buchanan
- Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia.
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Li R, Wang C, Tong J, Su Y, Lin Y, Zhou X, Ye L. WNT6 promotes the migration and differentiation of human dental pulp cells partly through c-Jun N-terminal kinase signaling pathway. J Endod 2014; 40:943-8. [PMID: 24935540 DOI: 10.1016/j.joen.2013.12.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Revised: 12/03/2013] [Accepted: 12/17/2013] [Indexed: 01/09/2023]
Abstract
INTRODUCTION During the dental pulp repair process, human dental pulp cells (HDPCs) migrate to injury sites where they may differentiate into odontoblastlike cells. WNT6 plays a role in dental development and can activate a noncanonical pathway including the c-Jun N-terminal kinase (JNK) pathway. The mechanism of WNT6 in dental pulp repair is still unknown. The purpose of this study was to explore the potential role of the WNT6/JNK signaling pathway in the promotion of cell migration and the differentiation of HDPCs. METHODS The third passage of HDPCs were cultured in vitro and treated with WNT6 conditioned medium with or without the pretreatment of JNK inhibitor SP600125. The activation of JNK was detected by Western blot, the expression of c-Jun was quantified by reverse-transcription polymerase chain reaction, the migration of HDPCs was determined by wound healing and transwell migration assays, and the differentiation of HDPCs was investigated using alkaline phosphatase staining and alizarin red staining. The expression of odontogenesis-related genes such as Runt-related transcription factor 2, dentin sialophosphoprotein, and dentin matrix protein 1 was quantified. RESULTS WNT6 activates the JNK pathway in HDPCs and enhances cell migration, mineralization nodule formation, and alkaline phosphatase activation. WNT6 also increases the expression of Runt-related transcription factor 2, dentin sialophosphoprotein, and dentin matrix protein messenger RNA in HDPCs. Blockage of the JNK pathway in HDPCs decreases but does not completely abolish the cell migration and differentiation capacity induced by WNT6. CONCLUSIONS WNT6 activates the JNK signaling pathway in HDPCs, leading to migration and differentiation.
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Affiliation(s)
- Ruimin Li
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Chenglin Wang
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Juan Tong
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yingying Su
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China.
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Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response. Proc Natl Acad Sci U S A 2014; 111:2560-5. [PMID: 24550283 DOI: 10.1073/pnas.1320815111] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The cellular response to hypoxia is regulated by hypoxia-inducible factor-1α and -2α (HIF-1α and -2α). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α and promotes tumor growth and angiogenesis. Hypoxia induces a calpain-dependent cleavage of FLNA to generate a naturally occurring C-terminal fragment that accumulates in the cell nucleus. This fragment interacts with the N-terminal portion of HIF-1α spanning amino acid residues 1-390 but not with HIF-2α. In hypoxia this fragment facilitates the nuclear localization of HIF-1α, is recruited to HIF-1α target gene promoters, and enhances HIF-1α function, resulting in up-regulation of HIF-1α target gene expression in a hypoxia-dependent fashion. These results unravel an important mechanism that selectively regulates the nuclear accumulation and function of HIF-1α and potentiates angiogenesis and tumor progression.
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46
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Savoy RM, Ghosh PM. The dual role of filamin A in cancer: can't live with (too much of) it, can't live without it. Endocr Relat Cancer 2013; 20:R341-56. [PMID: 24108109 PMCID: PMC4376317 DOI: 10.1530/erc-13-0364] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Filamin A (FlnA) has been associated with actin as cytoskeleton regulator. Recently its role in the cell has come under scrutiny for FlnA's involvement in cancer development. FlnA was originally revealed as a cancer-promoting protein, involved in invasion and metastasis. However, recent studies have also found that under certain conditions, it prevented tumor formation or progression, confusing the precise function of FlnA in cancer development. Here, we try to decipher the role of FlnA in cancer and the implications for its dual role. We propose that differences in subcellular localization of FlnA dictate its role in cancer development. In the cytoplasm, FlnA functions in various growth signaling pathways, such as vascular endothelial growth factor, in addition to being involved in cell migration and adhesion pathways, such as R-Ras and integrin signaling. Involvement in these pathways and various others has shown a correlation between high cytoplasmic FlnA levels and invasive cancers. However, an active cleaved form of FlnA can localize to the nucleus rather than the cytoplasm and its interaction with transcription factors has been linked to a decrease in invasiveness of cancers. Therefore, overexpression of FlnA has a tumor-promoting effect, only when it is localized to the cytoplasm, whereas if FlnA undergoes proteolysis and the resulting C-terminal fragment localizes to the nucleus, it acts to suppress tumor growth and inhibit metastasis. Development of drugs to target FlnA and cause cleavage and subsequent localization to the nucleus could be a new and potent field of research in treating cancer.
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Affiliation(s)
- Rosalinda M Savoy
- Department of Urology, University of California Davis School of Medicine, University of California, 4860 Y Street, Suite 3500, Sacramento, California 95817, USA VA Northern California Health Care System, Mather, California, USA
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Filamin A regulates neuronal migration through brefeldin A-inhibited guanine exchange factor 2-dependent Arf1 activation. J Neurosci 2013; 33:15735-46. [PMID: 24089482 DOI: 10.1523/jneurosci.1939-13.2013] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Periventricular heterotopias is a malformation of cortical development, characterized by ectopic neuronal nodules around ventricle lining and caused by an initial migration defect during early brain development. Human mutations in the Filamin A (FLNA) and ADP-ribosylation factor guanine exchange factor 2 [ARFGEF2; encoding brefeldin-A-inhibited guanine exchange factor-2 (BIG2)] genes give rise to this disorder. Previously, we have reported that Big2 inhibition impairs neuronal migration and binds to FlnA, and its loss promotes FlnA phosphorylation. FlnA phosphorylation dictates FlnA-actin binding affinity and consequently alters focal adhesion size and number to effect neuronal migration. Here we show that FlnA loss similarly impairs migration, reciprocally enhances Big2 expression, but also alters Big2 subcellular localization in both null and conditional FlnA mice. FlnA phosphorylation promotes relocalization of Big2 from the Golgi toward the lipid ruffles, thereby activating Big2-dependent Arf1 at the cell membrane. Loss of FlnA phosphorylation or Big2 function impairs Arf1-dependent vesicle trafficking at the periphery, and Arf1 is required for maintenance of cell-cell junction connectivity and focal adhesion assembly. Loss of Arf1 activity disrupts neuronal migration and cell adhesion. Collectively, these studies demonstrate a potential mechanism whereby coordinated interactions between actin (through FlnA) and vesicle trafficking (through Big2-Arf) direct the assembly and disassembly of membrane protein complexes required for neuronal migration and neuroependymal integrity.
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48
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Piao G, Wu J. Mining featured biomarkers associated with prostatic carcinoma based on bioinformatics. Biomarkers 2013; 18:580-6. [DOI: 10.3109/1354750x.2013.827743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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49
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McGrath MJ, Binge LC, Sriratana A, Wang H, Robinson PA, Pook D, Fedele CG, Brown S, Dyson JM, Cottle DL, Cowling BS, Niranjan B, Risbridger GP, Mitchell CA. Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. Cancer Res 2013; 73:5066-79. [PMID: 23801747 DOI: 10.1158/0008-5472.can-12-4520] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.
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Affiliation(s)
- Meagan J McGrath
- Department of Biochemistry and Molecular Biology and Immunology, Monash University, Clayton Victoria, Australia
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Yue J, Huhn S, Shen Z. Complex roles of filamin-A mediated cytoskeleton network in cancer progression. Cell Biosci 2013; 3:7. [PMID: 23388158 PMCID: PMC3573937 DOI: 10.1186/2045-3701-3-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 01/10/2013] [Indexed: 01/08/2023] Open
Abstract
Filamin-A (FLNA), also called actin-binding protein 280 (ABP-280), was originally identified as a non-muscle actin binding protein, which organizes filamentous actin into orthogonal networks and stress fibers. Filamin-A also anchors various transmembrane proteins to the actin cytoskeleton and provides a scaffold for a wide range of cytoplasmic and nuclear signaling proteins. Intriguingly, several studies have revealed that filamin-A associates with multiple non-cytoskeletal proteins of diverse function and is involved in several unrelated pathways. Mutations and aberrant expression of filamin-A have been reported in human genetic diseases and several types of cancer. In this review, we discuss the implications of filamin-A in cancer progression, including metastasis and DNA damage response.
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Affiliation(s)
- Jingyin Yue
- Department of Radiation Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA.
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