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1
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Asif M, Alvi SS, Azaz T, Khan AR, Tiwari B, Hafeez BB, Nasibullah M. Novel Functionalized Spiro [Indoline-3,5'-pyrroline]-2,2'dione Derivatives: Synthesis, Characterization, Drug-Likeness, ADME, and Anticancer Potential. Int J Mol Sci 2023; 24:ijms24087336. [PMID: 37108498 PMCID: PMC10139052 DOI: 10.3390/ijms24087336] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/29/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a-4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed that among all derivatives of SOXs (4a-4h), 4a has a substantial binding affinity (∆G) -6.65, -6.55, -8.73, and -7.27 Kcal/mol with CD-44, EGFR, AKR1D1, and HER-2, respectively. A functional study demonstrated that SOX 4a has a substantial impact on human cancer cell phenotypes exhibiting abnormality in cytoplasmic and nuclear architecture as well as granule formation leading to cell death. SOX 4a treatment robustly induced reactive oxygen species (ROS) generation in cancer cells as observed by enhanced DCFH-DA signals. Overall, our results suggest that SOX (4a) targets CD-44, EGFR, AKR1D1, and HER-2 and induces ROS generation in cancer cells. We conclude that SOX (4a) could be explored as a potential chemotherapeutic molecule against various cancers in appropriate pre-clinical in vitro and in vivo model systems.
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Affiliation(s)
- Mohd Asif
- Department of Chemistry, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Sahir Sultan Alvi
- Department of Immunology and Microbiology, South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Tazeen Azaz
- Department of Biological and Synthetic Chemistry, Centre of Biomedical Research, SGPGIMS-Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India
| | - Abdul Rahman Khan
- Department of Chemistry, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Bhoopendra Tiwari
- Department of Biological and Synthetic Chemistry, Centre of Biomedical Research, SGPGIMS-Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India
| | - Bilal Bin Hafeez
- Department of Immunology and Microbiology, South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Malik Nasibullah
- Department of Chemistry, Integral University, Lucknow 226026, Uttar Pradesh, India
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2
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Gilloteaux DJ, Jamison JM, Summers JL, Taper HS. Xenografts on nude mouse diaphragm of human DU145 prostate carcinoma cells: mesothelium removal by outgrowths and angiogenesis. Ultrastruct Pathol 2022; 46:413-438. [PMID: 36165802 DOI: 10.1080/01913123.2022.2115596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Human prostate carcinoma DU145 cells, androgen-independent malignant cells, implanted in the athymic nu/nu male mouse, developed numerous tumors on peritoneal and retro-peritoneal organs whose growth aspects and vascular supply have yet to be investigated with fine structure techniques. A series of necropsies from moribund implanted mice diaphragms were examined with light, scanning, and transmission electron microscopy. DU145 xenografts installations, far away from the implanted site, were described as the smallest installation to large diaphragm outgrowths in moribund mice. Carcinomas did not show extracellular matrix and, reaching more than 0.15 mm in thickness, they revealed new structures in these outgrowths. Voids to be gland-like structures with mediocre secretion and, unexpectedly, intercellular spaces connected with fascicles of elongated DU145 cells that merged with a vascular supply originated from either the tumor cells and/or some perimysium vessels. In the largest carcinomas, most important vascular invasions coincidently accompanied the mouse lethality, similarly to human cancers. This androgen-independent model would be useful to study tumor outgrowth's changes related to testing anticancer strategy, including anti-angiogenic therapies involving toxicity, simultaneously with those of other vital organs with combined biomolecular and fine structure techniques.
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Affiliation(s)
- Dr Jacques Gilloteaux
- Department of Anatomical Sciences, St Georges' University International School of Medicine, KB Taylor Global Scholar's Program, Newcastle upon Tyne, UK, NE1 8JG.,Unit of Research in Molecular Physiology (URPhyM), NARILIS, Université de Namur, Namur, Belgium, 5000.,Department of Anatomical Sciences, Ohio Medical University (NEOMed/Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA, 44272
| | - James M Jamison
- Department of Urology, Ohio Medical University (NEOMed/Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA, 44272.,St Thomas Hospital, The Apatone Development Center, Summa Research Foundation, Akron, OH, USA, 44310
| | - Jack L Summers
- Department of Urology, Ohio Medical University (NEOMed/Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA, 44272.,St Thomas Hospital, The Apatone Development Center, Summa Research Foundation, Akron, OH, USA, 44310
| | - Henryk S Taper
- Laboratoire de Pharmacologie Toxicologique et Cancérologique, School of Pharmacy, Université Catholique de Louvain, Brussels, Belgium, 1200
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3
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Vaquero J, Pavy A, Gonzalez-Sanchez E, Meredith M, Arbelaiz A, Fouassier L. Genetic alterations shaping tumor response to anti-EGFR therapies. Drug Resist Updat 2022; 64:100863. [DOI: 10.1016/j.drup.2022.100863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Schneider R, Gademann G, Ochel HJ, Neumann K, Jandrig B, Hass P, Walke M, Schostak M, Brunner T, Christoph F. Functional and mutational analysis after radiation and cetuximab treatment on prostate carcinoma cell line DU145. Radiat Oncol 2021; 16:137. [PMID: 34321039 PMCID: PMC8317395 DOI: 10.1186/s13014-021-01859-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 07/12/2021] [Indexed: 12/03/2022] Open
Abstract
Background Epidermal Growth Factor Receptor is often overexpressed in advanced prostate carcinoma. In-vitro-studies in prostate carcinoma cell line DU145 have demonstrated increased sensibility to radiation after cetuximab treatment, but clinical data are not sufficient to date. Methods We analyzed effects of radiation and cetuximab in DU145 and A431 using proliferation, colony-forming-unit- and annexin-V-apoptosis-assays. Changes in protein expression of pEGFR and pERK1/2 after radiation and cetuximab treatment were analyzed. Using NGS we also investigated the impact of cetuximab long-term treatment. Results Cell counts in DU145 were reduced by 44% after 4 Gy (p = 0.006) and 55% after 4 Gy and cetuximab (p < 0.001). The surviving fraction (SF) was 0.69 after 2 Gy, 0.41 after 4 Gy and 0.15 after 6 Gy (each p < 0.001). Cetuximab treatment did not alter significantly growth reduction in 4 Gy radiated DU145 cells, p > 0.05 or SF, p > 0.05, but minor effects on apoptotic cell fraction in DU145 were detected. Using western blot, there were no detectable pEGFR and pERK1/2 protein signals after cetuximab treatment. No RAS mutation or HER2 amplification was detected, however a TP53 gen-mutation c.820G > T was found. Conclusions Radiation inhibits cell-proliferation and colony-growth and induces apoptosis in DU145. Despite blocking MAP-Kinase-pathway using cetuximab, no significant radiation-sensitizing-effect was detected. Cetuximab treatment did not induce resistance-mutations. Further research must clarify which combination of anti-EGFR treatment strategies can increase radiation-sensitizing-effects.
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Affiliation(s)
- Raik Schneider
- Department of Radiotherapy, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany. .,Merck Serono Oncology, Darmstadt, Germany.
| | - Günther Gademann
- Department of Radiotherapy, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany
| | - Hans-Joachim Ochel
- Department of Radiotherapy, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany
| | - Karsten Neumann
- Department of Pathology, Hospital Dessau-Rosslau, Dessau, Germany
| | - Burkhard Jandrig
- Department of Urology, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany
| | - Peter Hass
- Department of Radiotherapy, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany
| | - Mathias Walke
- Department of Radiotherapy, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany
| | - Martin Schostak
- Department of Urology, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany
| | - Thomas Brunner
- Department of Radiotherapy, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany
| | - Frank Christoph
- Department of Urology, Otto-von-Guericke-University Magdeburg, University Hospital, Magdeburg, Germany.,Urology City West, Berlin, Germany
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5
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Tata P, Gondaliya P, Sunkaria A, Srivastava A, Kalia K. Modulation of CD44, EGFR and RAC Pathway Genes (WAVE Complex) in Epithelial Cancers. Curr Pharm Des 2019; 25:833-848. [PMID: 30799784 DOI: 10.2174/1381612825666190222143044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/13/2019] [Indexed: 12/12/2022]
Abstract
Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers play an immense role in the tumor biology through Epithelial-Mesenchymal Transition (EMT) process. Receptor tyrosine kinase, as well as phosphatidyl ionositol-3 kinase pathways, play an important role in the regulation of cell proliferation, survival, and differentiation during EMT. Till date, numerous studies have shown modulation in the expression profile of potential targets like CD44, EGFR, and Rac in epithelial cancers. CD44 interacts with EGFR and recruits other molecules which further activate the Rac pathway intermediates. This review mainly focused on modulation of genes like CD44, EGFR, and Rac pathway intermediates which play a crucial role in the tumor progression, metastasis, proliferation, and invasion characteristics in epithelial cancers with EMT properties. Hence, targeting Rac pathway might be a more strategically relevant approach in treating epithelial cancers.
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Affiliation(s)
- Pranathi Tata
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Piyush Gondaliya
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Aditya Sunkaria
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Akshay Srivastava
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Kiran Kalia
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
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6
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Ochoa S, Martínez-Pérez E, Zea DJ, Molina-Vila MA, Marino-Buslje C. Comutation and exclusion analysis in human tumors: A tool for cancer biology studies and for rational selection of multitargeted therapeutic approaches. Hum Mutat 2019; 40:413-425. [PMID: 30629309 DOI: 10.1002/humu.23705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 12/20/2018] [Accepted: 01/03/2019] [Indexed: 11/11/2022]
Abstract
Malignant tumors originate from somatic mutations and other genomic and epigenomic alterations, which lead to loss of control of the cellular circuitry. These alterations present patterns of co-occurrence and mutual exclusivity that can influence prognosis and modify response to drugs, highlighting the need for multitargeted therapies. Studies in this area have generally focused in particular malignancies and considered whole genes instead of specific mutations, ignoring the fact that different alterations in the same gene can have widely different effects. Here, we present a comprehensive analysis of co-dependencies of individual somatic mutations in the whole spectrum of human tumors. Combining multitesting with conditional and expected mutational probabilities, we have discovered rules governing the codependencies of driver and nondriver mutations. We also uncovered pairs and networks of comutations and exclusions, some of them restricted to certain cancer types and others widespread. These pairs and networks are not only of basic but also of clinical interest, and can be of help in the selection of multitargeted antitumor therapies. In this respect, recurrent driver comutations suggest combinations of drugs that might be effective in the clinical setting, while recurrent exclusions indicate combinations unlikely to be useful.
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Affiliation(s)
- Soledad Ochoa
- Fundación Instituto Leloir, Avda. Patricias Argentinas 435, Buenos Aires, Argentina
| | | | - Diego Javier Zea
- Fundación Instituto Leloir, Avda. Patricias Argentinas 435, Buenos Aires, Argentina
| | - Miguel Angel Molina-Vila
- Laboratory of Onchology, Hospital Universitario Quirón Dexeus, C/Sabino Arana 5-19, 08028, Barcelona, Spain
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7
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Tsai YC, Zeng T, Abou-Kheir W, Yeh HL, Yin JJ, Lee YC, Chen WY, Liu YN. Disruption of ETV6 leads to TWIST1-dependent progression and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in prostate cancer. Mol Cancer 2018; 17:42. [PMID: 29455655 PMCID: PMC5817720 DOI: 10.1186/s12943-018-0785-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 02/01/2018] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND ETS variant gene 6 (ETV6) is a putative tumor suppressor and repressed by epidermal growth factor receptor (EGFR) signaling in prostate cancer. Since EGFR antagonists seem ineffective in castration-resistant prostate cancer (CRPC), we aim to study the role of ETV6 in the development of drug resistance. METHODS Etv6 target gene was validated by ChIP and promoter reporter assays. Correlation of ETV6 and TWIST1 was analyzed in human clinical datasets and tissue samples. Migration, invasion, and metastasis assays were used to measure the cellular responses after perturbation of ETV6 -TWIST1 axis. Proliferation and tumor growth in xenograft model were performed to evaluate the drug sensitivities of EGFR-tyrosine kinase inhibitors (TKIs). RESULTS ETV6 inhibits TWIST1 expression and disruption of ETV6 promotes TWIST1-dependent malignant phenotypes. Importantly, ETV6 is required to the anti-proliferation effects of EGFR-TKIs, partly due to the inhibitory function of ETV6 on TWIST1. We also found that EGFR-RAS signaling is tightly controlled by ETV6, supporting its role in TKI sensitivity. CONCLUSIONS Our study demonstrates that disruption of ETV6 contributes to EGFR-TKI resistance, which is likely due to derepression of TWIST1 and activation of EGFR-RAS signaling. Our results implicate ETV6 as a potential marker for predicting efficacy of an EGFR-targeted anticancer approach. Combination treatment of TWIST1 inhibitors could sensitize the anti-proliferation effects of EGFR-TKIs.
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Affiliation(s)
- Yuan-Chin Tsai
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan
| | - Tao Zeng
- Department of Urology, The People's Hospital of Jiangxi Province, Nanchang, People's Republic of China
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hsiu-Lien Yeh
- Institute of Information System and Applications, National Tsing Hua University, Hsinchu, Taiwan
| | - Juan Juan Yin
- Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yi-Chao Lee
- Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan
| | - Wei-Yu Chen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.
| | - Yen-Nien Liu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.
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8
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Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The "Rotation Model". Cells 2017; 6:cells6020013. [PMID: 28574446 PMCID: PMC5492017 DOI: 10.3390/cells6020013] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 05/17/2017] [Accepted: 05/31/2017] [Indexed: 01/17/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility, and differentiation. The dysregulated activation of the receptor is often implicated in human cancers. EGFR is synthesized as a single-pass transmembrane protein, which consists of an extracellular ligand-binding domain and an intracellular kinase domain separated by a single transmembrane domain. The receptor is activated by a variety of polypeptide ligands such as epidermal growth factor and transforming growth factor α. It has long been thought that EGFR is activated by ligand-induced dimerization of the receptor monomer, which brings intracellular kinase domains into close proximity for trans-autophosphorylation. An increasing number of diverse studies, however, demonstrate that EGFR is present as a pre-formed, yet inactive, dimer prior to ligand binding. Furthermore, recent progress in structural studies has provided insight into conformational changes during the activation of a pre-formed EGFR dimer. Upon ligand binding to the extracellular domain of EGFR, its transmembrane domains rotate or twist parallel to the plane of the cell membrane, resulting in the reorientation of the intracellular kinase domain dimer from a symmetric inactive configuration to an asymmetric active form (the “rotation model”). This model is also able to explain how oncogenic mutations activate the receptor in the absence of the ligand, without assuming that the mutations induce receptor dimerization. In this review, we discuss the mechanisms underlying the ligand-induced activation of the preformed EGFR dimer, as well as how oncogenic mutations constitutively activate the receptor dimer, based on the rotation model.
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9
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Wu X, Deng F, Li Y, Daniels G, Du X, Ren Q, Wang J, Wang LH, Yang Y, Zhang V, Zhang D, Ye F, Melamed J, Monaco ME, Lee P. ACSL4 promotes prostate cancer growth, invasion and hormonal resistance. Oncotarget 2016; 6:44849-63. [PMID: 26636648 PMCID: PMC4792596 DOI: 10.18632/oncotarget.6438] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 10/21/2015] [Indexed: 12/27/2022] Open
Abstract
Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and β-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC.
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Affiliation(s)
- Xinyu Wu
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Fangming Deng
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Yirong Li
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Garrett Daniels
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Xinxin Du
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Qinghu Ren
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Jinhua Wang
- Department of Pediatrics, New York University School of Medicine, New York, NY, USA.,NYU Cancer Institute, New York University School of Medicine, New York, NY, USA.,NYU Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, NY, USA
| | - Ling Hang Wang
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Yang Yang
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Valerio Zhang
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - David Zhang
- Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
| | - Fei Ye
- Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
| | - Jonathan Melamed
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Marie E Monaco
- Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, USA.,VA New York Harbor Healthcare System, New York University School of Medicine, New York, NY, USA
| | - Peng Lee
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,NYU Cancer Institute, New York University School of Medicine, New York, NY, USA.,Department of Urology, New York University School of Medicine, New York, NY, USA.,VA New York Harbor Healthcare System, New York University School of Medicine, New York, NY, USA
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10
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Graça I, Sousa EJ, Costa-Pinheiro P, Vieira FQ, Torres-Ferreira J, Martins MG, Henrique R, Jerónimo C. Anti-neoplastic properties of hydralazine in prostate cancer. Oncotarget 2014; 5:5950-64. [PMID: 24797896 PMCID: PMC4171604 DOI: 10.18632/oncotarget.1909] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/16/2014] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation levels, with concomitant transcript re-expression, was also observed. Interestingly, hydralazine restored androgen receptor expression, with upregulation of its target p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor signaling pathway is likely to be the main mechanism of hydralazine action in DU145 cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of PCa cells, and might constitute a useful therapeutic tool.
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Affiliation(s)
- Inês Graça
- Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto
- Departments of School of Allied Health Sciences ESTSP, Polytechnic of Porto
| | - Elsa J Sousa
- Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto
| | - Pedro Costa-Pinheiro
- Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto
| | - Filipa Q Vieira
- Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto
- Departments of School of Allied Health Sciences ESTSP, Polytechnic of Porto
| | - Jorge Torres-Ferreira
- Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto
- Department of Pathology, Portuguese Oncology Institute-Porto
| | - Maria Gabriela Martins
- Department of Hematology - Laboratory of Flow Cytometry, Portuguese Oncology Institute-Porto
| | - Rui Henrique
- Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto
- Department of Pathology, Portuguese Oncology Institute-Porto
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto
| | - Carmen Jerónimo
- Cancer Biology & Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto
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11
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Daniels G, Li Y, Gellert LL, Zhou A, Melamed J, Wu X, Zhang X, Zhang D, Meruelo D, Logan SK, Basch R, Lee P. TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth. Endocr Relat Cancer 2014; 21:127-42. [PMID: 24243687 PMCID: PMC3947037 DOI: 10.1530/erc-13-0293] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Androgen receptor (AR), a steroid hormone receptor, is critical for prostate cancer growth. However, activation of AR by androgens can also lead to growth suppression and differentiation. Transcriptional cofactors play an important role in this switch between proliferative and anti-proliferative AR target gene programs. Transducin β-like-related protein 1 (TBLR1), a core component of the nuclear receptor corepressor complex, shows both corepressor and coactivator activities on nuclear receptors, but little is known about its effects on AR and prostate cancer. We characterized TBLR1 as a coactivator of AR in prostate cancer cells and determined that the activation is dependent on both phosphorylation and 19S proteosome. We showed that TBLR1 physically interacts with AR and directly occupies the androgen-response elements of the affected AR target genes in an androgen-dependent manner. TBLR1 is primarily localized in the nucleus in benign prostate cells and nuclear expression is significantly reduced in prostate cancer cells in culture. Similarly, in human tumor samples, the expression of TBLR1 in the nucleus is significantly reduced in the malignant glands compared with the surrounding benign prostatic glands (P<0.005). Stable ectopic expression of nuclear TBLR1 leads to androgen-dependent growth suppression of prostate cancer cells in vitro and in vivo by selective activation of androgen-regulated genes associated with differentiation (e.g. KRT18) and growth suppression (e.g. NKX3-1), but not cell proliferation of the prostate cancer. Understanding the molecular switches involved in the transition from AR-dependent growth promotion to AR-dependent growth suppression will lead to more successful treatments for prostate cancer.
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Affiliation(s)
- Garrett Daniels
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Yirong Li
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Lan Lin Gellert
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Albert Zhou
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Jonathan Melamed
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Xinyu Wu
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Xinming Zhang
- Department of Pathology, New York University School of Medicine, New York, NY
| | - David Zhang
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - Daniel Meruelo
- Department of Pathology, New York University School of Medicine, New York, NY
- NYU Cancer Institute, New York University School of Medicine, New York, NY
| | - Susan K. Logan
- NYU Cancer Institute, New York University School of Medicine, New York, NY
- Department of Urology, New York University School of Medicine, New York, NY
- Department of Pharmacology, New York University School of Medicine, New York, NY
| | - Ross Basch
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Peng Lee
- Department of Pathology, New York University School of Medicine, New York, NY
- NYU Cancer Institute, New York University School of Medicine, New York, NY
- Department of Pharmacology, New York University School of Medicine, New York, NY
- New York Harbor Healthcare System, New York University School of Medicine, New York, NY
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12
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Mazzucchelli S, Truffi M, Fiandra L, Sorrentino L, Corsi F. Targeted approaches for HER2 breast cancer therapy: News from nanomedicine? World J Pharmacol 2014; 3:72. [DOI: 10.5497/wjp.v3.i4.72] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 08/29/2014] [Accepted: 09/24/2014] [Indexed: 02/07/2023] Open
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13
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HER. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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14
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Wu X, Li Y, Wang J, Wen X, Marcus MT, Daniels G, Zhang DY, Ye F, Wang LH, Du X, Adams S, Singh B, Zavadil J, Lee P, Monaco ME. Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. PLoS One 2013; 8:e77060. [PMID: 24155918 PMCID: PMC3796543 DOI: 10.1371/journal.pone.0077060] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 09/05/2013] [Indexed: 12/16/2022] Open
Abstract
The purpose of this study was to determine the role of long-chain fatty acyl-CoA synthetase 4 (ACSL4) in breast cancer. Public databases were utilized to analyze the relationship between ACSL4 mRNA expression and the presence of steroid hormone and human epidermal growth factor receptor 2 (HER2) in both breast cancer cell lines and tissue samples. In addition, cell lines were utilized to assess the consequences of either increased or decreased levels of ACSL4 expression. Proliferation, migration, anchorage-independent growth and apoptosis were used as biological end points. Effects on mRNA expression and signal transduction pathways were also monitored. A meta-analysis of public gene expression databases indicated that ACSL4 expression is positively correlated with a unique subtype of triple negative breast cancer (TNBC), characterized by the absence of androgen receptor (AR) and therefore referred to as quadruple negative breast cancer (QNBC). Results of experiments in breast cancer cell lines suggest that simultaneous expression of ACSL4 and a receptor is associated with hormone resistance. Forced expression of ACSL4 in ACSL4-negative, estrogen receptor α (ER)-positive MCF-7 cells resulted in increased growth, invasion and anchorage independent growth, as well as a loss of dependence on estrogen that was accompanied by a reduction in the levels of steroid hormone receptors. Sensitivity to tamoxifen, triacsin C and etoposide was also attenuated. Similarly, when HER2-positive, ACSL4-negative, SKBr3 breast cancer cells were induced to express ACSL4, the proliferation rate increased and the apoptotic effect of lapatinib was reduced. The growth stimulatory effect of ACSL4 expression was also observed in vivo in nude mice when MCF-7 control and ACSL4-expressing cells were utilized to induce tumors. Our data strongly suggest that ACSL4 can serve as both a biomarker for, and mediator of, an aggressive breast cancer phenotype.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Apoptosis/genetics
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/classification
- Breast Neoplasms/drug therapy
- Breast Neoplasms/enzymology
- Breast Neoplasms/genetics
- Cell Adhesion
- Cell Line, Tumor
- Cell Proliferation
- Coenzyme A Ligases/genetics
- Coenzyme A Ligases/metabolism
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Estrogen Receptor alpha/genetics
- Estrogen Receptor alpha/metabolism
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic/drug effects
- Hormones/pharmacology
- Humans
- Mice
- Mice, Nude
- Neoplasm Invasiveness
- Oligonucleotide Array Sequence Analysis
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Reproducibility of Results
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Affiliation(s)
- Xinyu Wu
- Department of Neuroscience & Physiology, New York University School of Medicine, New York, New York, United States of America
| | - Yirong Li
- Department of Pathology, New York University School of Medicine, New York, New York, United States of America
| | - Jinhua Wang
- Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America
- NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America
- NYU Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, United States of America
| | - Xin Wen
- Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America
- NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America
- NYU Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, United States of America
| | - Max T. Marcus
- Department of Neuroscience & Physiology, New York University School of Medicine, New York, New York, United States of America
| | - Garrett Daniels
- Department of Pathology, New York University School of Medicine, New York, New York, United States of America
| | - David Y. Zhang
- Department of Pathology, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Fei Ye
- Department of Pathology, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Ling Hang Wang
- Department of Pathology, New York University School of Medicine, New York, New York, United States of America
| | - Xinxin Du
- Department of Pathology, New York University School of Medicine, New York, New York, United States of America
| | - Sylvia Adams
- Department of Medicine, New York University School of Medicine, New York, New York, United States of America
- NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America
| | - Baljit Singh
- Department of Pathology, New York University School of Medicine, New York, New York, United States of America
- NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America
| | - Jiri Zavadil
- Department of Pathology, New York University School of Medicine, New York, New York, United States of America
- NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America
| | - Peng Lee
- Department of Pathology, New York University School of Medicine, New York, New York, United States of America
- NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America
- VA New York Harbor Healthcare System, New York, New York, United States of America
- *E-mail: (MM); (PL)
| | - Marie E. Monaco
- Department of Neuroscience & Physiology, New York University School of Medicine, New York, New York, United States of America
- NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America
- VA New York Harbor Healthcare System, New York, New York, United States of America
- *E-mail: (MM); (PL)
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15
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Rybak AP, Ingram AJ, Tang D. Propagation of human prostate cancer stem-like cells occurs through EGFR-mediated ERK activation. PLoS One 2013; 8:e61716. [PMID: 23620784 PMCID: PMC3631151 DOI: 10.1371/journal.pone.0061716] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 03/17/2013] [Indexed: 01/06/2023] Open
Abstract
Prostate cancer stem-like cells (PCSCs) are being intensely investigated largely owing to their contributions towards prostate tumorigenesis, however, our understanding of PCSC biology, including their critical pathways, remains incompletely understood. While epidermal growth factor (EGF) is widely used in maintaining PCSC cells in vitro, the importance of EGF-dependent signaling and its downstream pathways in PCSC self-renewal are not well characterized. By investigating DU145 sphere cells, a population of prostate cancer cells with stem-like properties, we report here that epidermal growth factor receptor (EGFR) signaling plays a critical role in the propagation of DU145 PCSCs. Activation of EGFR signaling via addition of EGF and ectopic expression of a constitutively-active EGFR mutant (EGFRvIII) increased sphere formation. Conversely, inhibition of EGFR signaling by using EGFR inhibitors (AG1478 and PD168393) and knockdown of EGFR significantly inhibited PCSC self-renewal. Consistent with the MEK-ERK pathway being a major target of EGFR signaling, activation of the MEK-ERK pathway contributed to EGFR-facilitated PCSC propagation. Modulation of EGFR signaling affected extracellular signal-related kinase (ERK) activation. Inhibition of ERK activation through multiple approaches, including treatment with the MEK inhibitor U0126, ectopic expression of dominant-negative MEK1(K97M), and knockdown of either ERK1 or ERK2 resulted in a robust reduction in PCSC propagation. Collectively, the present study provides evidence that EGFR signaling promotes PCSC self-renewal, in part, by activating the MEK-ERK pathway.
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Affiliation(s)
- Adrian P Rybak
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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16
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Catalanotti F, Solit DB, Pulitzer MP, Berger MF, Scott SN, Iyriboz T, Lacouture ME, Panageas KS, Wolchok JD, Carvajal RD, Schwartz GK, Rosen N, Chapman PB. Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. Clin Cancer Res 2013; 19:2257-64. [PMID: 23444215 PMCID: PMC3932005 DOI: 10.1158/1078-0432.ccr-12-3476] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated. EXPERIMENTAL DESIGN We conducted a phase II trial in patients with melanoma whose tumors harbored a BRAF mutation. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg per os twice daily. Pretreatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach. RESULTS The high pAKT cohort was closed after no responses were seen in the first 10 patients. The incidence of low pAKT melanoma tumors was low (∼25% of melanomas tested) and this cohort was eventually closed because of poor accrual. However, among the five patients with melanoma accrued in the low pAKT cohort, there was one partial response (PR). Two other patients had near PRs before undergoing surgical resection of residual disease (one patient) or discontinuation of treatment due to toxicity (one patient). Among the two nonresponding, low pAKT patients with melanoma, co-mutations in MAP2K1, NF1, and/or EGFR were detected. CONCLUSIONS Tumor regression was seen in three of five patients with BRAF-mutated, low pAKT melanomas; no responses were seen in the high pAKT cohort. These results provide rationale for co-targeting MEK and PI3K/AKT in patients with BRAF mutant melanoma whose tumors express high pAKT. However, the complexity of genetic changes in melanoma indicates that additional genetic information will be needed for optimal selection of patients likely to respond to MEK inhibitors.
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Affiliation(s)
- Federica Catalanotti
- The Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
| | - David B. Solit
- Department of Medicine, Memorial Sloan-Kettering Cancer Center
- The Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
| | | | | | | | - Tunc Iyriboz
- Department of Radiology, Memorial Sloan-Kettering Cancer Center
| | | | | | - Jedd D. Wolchok
- Department of Medicine, Memorial Sloan-Kettering Cancer Center
- The Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center
| | | | | | - Neal Rosen
- Department of Medicine, Memorial Sloan-Kettering Cancer Center
- Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center
| | - Paul B. Chapman
- Department of Medicine, Memorial Sloan-Kettering Cancer Center
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17
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Gilloteaux J, Jamison JM, Neal D, Arnold D, Taper HS, Summers JL. Human Prostate DU145 Carcinoma Cells Implanted in Nude Mice Remove the Peritoneal Mesothelium to Invade and Grow as Carcinomas. Anat Rec (Hoboken) 2012; 296:40-55. [DOI: 10.1002/ar.22607] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2012] [Revised: 06/25/2012] [Accepted: 07/23/2012] [Indexed: 11/07/2022]
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18
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McGinn OJ, Marinov G, Sawan S, Stern PL. CXCL12 receptor preference, signal transduction, biological response and the expression of 5T4 oncofoetal glycoprotein. J Cell Sci 2012; 125:5467-78. [PMID: 22956548 DOI: 10.1242/jcs.109488] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
CXCL12 is a pleiotropic chemokine capable of eliciting multiple signal transduction cascades and functions, via interaction with either CXCR4 or CXCR7. Factors that determine CXCL12 receptor preference, intracellular signalling route and biological response are poorly understood but are of central importance in the context of therapeutic intervention of the CXCL12 axis in multiple disease states. We have recently demonstrated that 5T4 oncofoetal glycoprotein facilitates functional CXCR4 expression leading to CXCL12 mediated chemotaxis in mouse embryonic cells. Using wild type (WT) and 5T4 knockout (5T4KO) murine embryonic fibroblasts (MEFs), we now show that CXCL12 binding to CXCR4 activates both the ERK and AKT pathways within minutes, but while these pathways are intact, they are non-functional in 5T4KO cells treated with CXCL12. Importantly, in the absence of 5T4 expression, CXCR7 is upregulated and becomes the predominant receptor for CXCL12, activating a distinct signal transduction pathway with slower kinetics involving transactivation of the epidermal growth factor receptor (EGFR), eliciting proliferation rather than chemotaxis. Thus the surface expression of 5T4 marks the use of the CXCR4 rather than the CXCR7 receptor, with distinct consequences for CXCL12 exposure, relevant to the spread and growth of a tumour. Consistent with this hypothesis, we have identified human small cell lung carcinoma cells with similar 5T4/CXCR7 reciprocity that is predictive of biological response to CXCL12 and determined that 5T4 expression is required for functional chemotaxis in these cells.
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Affiliation(s)
- Owen J McGinn
- Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester M13 9PT, UK
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19
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Abstract
Prostate cancer is a common malignancy in men, with a markedly variable clinical course. Somatic alterations in DNA drive the growth of prostate cancers and may underlie the behavior of aggressive versus indolent tumors. The accelerating application of genomic technologies over the last two decades has identified mutations that drive prostate cancer formation, progression, and therapeutic resistance. Here, we discuss exemplary somatic mutations in prostate cancer, and highlight mutated cellular pathways with biological and possible therapeutic importance. Examples include mutated genes involved in androgen signaling, cell cycle regulation, signal transduction, and development. Some genetic alterations may also predict the clinical course of disease or response to therapy, although the molecular heterogeneity of prostate tumors poses challenges to genomic biomarker identification. The widespread application of massively parallel sequencing technology to the analysis of prostate cancer genomes should continue to advance both discovery-oriented and diagnostic avenues.
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Affiliation(s)
- Sylvan C. Baca
- Harvard Medical School, Boston,MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA, USA
- The Broad Institute of MIT and Harvard, Cambridge,MA, USA
| | - Levi A. Garraway
- Harvard Medical School, Boston,MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA, USA
- The Broad Institute of MIT and Harvard, Cambridge,MA, USA
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute,Boston, MA, USA
- *Correspondence: Levi A. Garraway, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. e-mail:
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20
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Li Y, Ligr M, McCarron JP, Daniels G, Zhang D, Zhao X, Ye F, Wang J, Liu X, Osman I, Mencher SK, Lepor H, Wang LG, Lee P. Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion. Clin Cancer Res 2011; 17:4414-24. [PMID: 21606178 PMCID: PMC3196615 DOI: 10.1158/1078-0432.ccr-11-0431] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC. EXPERIMENTAL DESIGN The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts. RESULTS Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC(50) between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha. CONCLUSION Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone-refractory PC with minimal side effects.
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Affiliation(s)
- Yirong Li
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Martin Ligr
- Department of Pathology, New York University School of Medicine, New York, NY
| | - James P McCarron
- Department of Urology, Presbyterian-Cornell Medical Center, New York, NY
| | - Garrett Daniels
- Department of Pathology, New York University School of Medicine, New York, NY
| | - David Zhang
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - Xin Zhao
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - Fei Ye
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - Jinhua Wang
- NYU Cancer Institute, New York University School of Medicine, New York, NY
| | - Xiaomei Liu
- NYU Cancer Institute, New York University School of Medicine, New York, NY
| | - Iman Osman
- NYU Cancer Institute, New York University School of Medicine, New York, NY
- Department of Urology, New York University School of Medicine, New York, NY
| | | | - Hebert Lepor
- Department of Urology, New York University School of Medicine, New York, NY
| | - Long G Wang
- NYU Cancer Institute, New York University School of Medicine, New York, NY
- Natrogen Therapeutics, New York, NY
| | - Peng Lee
- Department of Pathology, New York University School of Medicine, New York, NY
- NYU Cancer Institute, New York University School of Medicine, New York, NY
- Department of Urology, New York University School of Medicine, New York, NY
- New York Harbor Healthcare System, New York, NY
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21
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Abstract
Frequent mutations in the GNAQ, MMP8, Akt3, EGFR, and PIK3R1 genes have been reported in human cancers but mostly have not been well examined in thyroid cancer. Selected exons of GNAQ, MMP8, AKT3, EGFR, and PIK3R1 genes were sequenced in various thyroid cancers. We found a G2203A EGFR mutation, resulting in a G735S amino acid change, in one of 21 (5%) papillary thyroid cancer samples. We did not find any mutation in the MMP8 gene, but observed a frequent SNP A259G (K87E) genotype switch in various types of thyroid cancer samples. We did not find any mutation in the GNAQ, AKT3, and PIK3R1 genes in various types of thyroid cancer. No mutation in these genes was found in 12 cell lines derived from various types of thyroid cancer. Therefore, unlike in other cancers, mutations in these genes are uncommon in thyroid cancer.
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Affiliation(s)
- Avaniyapuram Kannan Murugan
- Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, 1830, East Monument Street, Suite 333, Baltimore, MD 21287, USA
| | - Jianli Dong
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Jingwu Xie
- Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Mingzhao Xing
- Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, 1830, East Monument Street, Suite 333, Baltimore, MD 21287, USA
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22
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Peng Y, Li Y, Gellert LL, Zou X, Wang J, Singh B, Xu R, Chiriboga L, Daniels G, Pan R, Zhang DY, Garabedian MJ, Schneider RJ, Wang Z, Lee P. Androgen receptor coactivator p44/Mep50 in breast cancer growth and invasion. J Cell Mol Med 2011; 14:2780-9. [PMID: 19840198 PMCID: PMC3822728 DOI: 10.1111/j.1582-4934.2009.00936.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Hormones and their receptors play an important role in the development and progression of breast carcinoma. Although the primary focus has been on oestrogen and oestrogen receptor (ER), androgen, androgen receptor (AR) and its coactivator(s) have been implicated in tumorigenesis of breast carcinoma and warrant further investigation. AR coactivator p44/Mep50 is identified as a subunit of methylosome complex and lately characterized as an AR coactivator that enhances AR mediated transcription activity in a ligand dependent manner. In prostate cancer, p44 is expressed in the nucleus of benign epithelia and translocated into the cytoplasm in cancer cells. Furthermore, nuclear expression of p44 inhibits prostate cancer growth. In this report, we examined the expression and function of p44 in breast cancer. In addition to being an AR coactivator, p44 also functions as an ER coactivator. In contrast to findings in prostate cancer, the expression of p44 shows strong cytoplasmic expression in morphologically normal terminal ductal lobular units, while nuclear p44 is observed in both ductal carcinoma in situ and invasive carcinoma. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in MCF7 breast cancer cells in the presence of oestrogen and the process is ERα dependent. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during tumorigenesis in breast.
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Affiliation(s)
- Yi Peng
- Department of Pathology, New York University School of Medicine, New York, NY 10010, USA
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23
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Peraldo-Neia C, Migliardi G, Mello-Grand M, Montemurro F, Segir R, Pignochino Y, Cavalloni G, Torchio B, Mosso L, Chiorino G, Aglietta M. Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. BMC Cancer 2011; 11:31. [PMID: 21266046 PMCID: PMC3040720 DOI: 10.1186/1471-2407-11-31] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 01/25/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Activating mutations of the epidermal growth factor receptor (EGFR) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease. METHODS Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples. RESULTS EGFR protein overexpression (EGFRhigh) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFRhigh tumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFRlow). Microarray analysis did not reveal any differences in gene expression between EGFRhigh and EGFRlow tumours. Conversely, in EGFRhigh tumours, we were able to identify a 79 gene signature distinguishing mutated from non-mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFRhigh (n=3) and mutated/EGFRlow tumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression. CONCLUSIONS Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.
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Affiliation(s)
- Caterina Peraldo-Neia
- Department of Clinical Oncology, University of Torino Medical School, Institute for Cancer Research and Treatment, Candiolo, Turin, Italy.
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24
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Pines G, Köstler WJ, Yarden Y. Oncogenic mutant forms of EGFR: lessons in signal transduction and targets for cancer therapy. FEBS Lett 2010; 584:2699-706. [PMID: 20388509 PMCID: PMC2892754 DOI: 10.1016/j.febslet.2010.04.019] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Revised: 04/07/2010] [Accepted: 04/08/2010] [Indexed: 11/30/2022]
Abstract
The EGF-receptor is frequently mutated in a large variety of tumors. Here we review the most frequent mutations and conclude that they commonly enhance the intrinsic tyrosine kinase activity, or they represent loss-of-function of suppressive regulatory domains. Interestingly, the constitutive activity of mutant receptors translates to downstream pathways, which are subtly different from those stimulated by the wild-type receptor. Cancer drugs intercepting EGFR signaling have already entered clinical application. Both kinase inhibitors specific to EGFR, and monoclonal antibodies to the receptor are described, along with experimental approaches targeting the HSP90 chaperone. Deeper understanding of signaling pathways downstream to mutant receptors will likely improve the outcome of current EGFR-targeted therapies, as well as help develop new drugs and combinations.
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Affiliation(s)
- Gur Pines
- Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
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25
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Gao X, Pang J, Li LY, Liu WP, Di JM, Sun QP, Fang YQ, Liu XP, Pu XY, He D, Li MT, Su ZL, Li BY. Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer. Oncogene 2010; 29:4555-66. [PMID: 20543870 DOI: 10.1038/onc.2010.213] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Metastasis is the chief cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. We used a proteomics approach to screen for metastasis-associated proteins and found that collapsin response mediator protein-4 (CRMP4) expression was inversely associated with the lymph node metastasis of prostate cancer (PCa). Subsequent in vitro and in vivo studies revealed that overexpression of CRMP4 not only suppressed the invasion ability of PCa cells, but also strongly inhibited tumor metastasis in an animal model. Furthermore, methylation of a CpG island within the promoter region of the CRMP4 gene is responsible for downregulation of CRMP4 expression. Thus, in this study, we show new function of CRMP4 as a metastasis-suppressor in PCa. The findings provide new mechanistic insights into metastasis and therapeutic potential for this most common male cancer.
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Affiliation(s)
- X Gao
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Molecular alterations of EGFR and PTEN in prostate cancer: association with high-grade and advanced-stage carcinomas. Mod Pathol 2010; 23:703-12. [PMID: 20208477 DOI: 10.1038/modpathol.2010.45] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Prostate cancer is the second cause of cancer-related death in men of the Western world. The potential prognostic role of the combined alterations in EGFR and PTEN in prostate cancer is not well established. It was the aim of the study to investigate this role. Prevalence of EGFR and PTEN somatic mutations, EGFR amplification and EGFR protein expression were investigated in a series of prostate adenocarcinomas, classified according to the current Gleason grading system. Mutational analysis revealed eight EGFR and three PTEN mutations in 98 (8%) and 92 (3%) prostate adenocarcinomas, respectively. The combined prevalence of EGFR-PTEN mutations was 11%. EGFR overexpression was present in 31% of adenocarcinomas, with a marginally significant difference (P=0.068) between Gleason grade < or =7 adenocarcinomas and Gleason grade > or =8 and metastatic adenocarcinomas. Four cases (4 of 31; 13%) had an EGFR gene gain due to chromosome 7 polysomy. In 35% of adenocarcinomas we found some type of EGFR-PTEN alteration, with a tendency to be associated with advanced-stage prostate adenocarcinomas (P=0.04). The IVS18+19 polymorphism was also associated with more advanced prostate adenocarcinomas. This is the first study reporting mutations of EGFR and PTEN in the same series of prostate adenocarcinomas. Protein overexpression is the most frequent EGFR abnormality. Mutations in EGFR and PTEN genes are a minor event, although prostate cancer represents the third neoplasm in which the EGFR gene mutations are more prevalent. Alterations in the EGFR-PTEN signaling pathway are present in a third of prostate adenocarcinomas, particularly affecting the more advanced cases.
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He M, Young CYF. Mutant epidermal growth factor receptor vIII increases cell motility and clonogenecity in a prostate cell line RWPE1. J Endocrinol Invest 2009; 32:272-8. [PMID: 19542748 DOI: 10.1007/bf03346466] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Epidermal growth faxtor receptor (EGFR)-vIII mutant has been demonstrated to over-express as prostatic neoplasms progressed from intraepithelial changes to metastatic disease. In this study, we transfected the EGFRvIII expression vector into an immortalized normal prostate epithelium cell line RWPE-1 and established stable transfectants. The cell growth, glandular morphogenesis, cell motility, and soft-agar colony formation efficiency were then studied. The results showed that EGFR-vIII mutation increased the RWPE1 cell motility and clone formation efficiency, while it had no significant effect on the cell growth when compared to non-transfected as well as mock transfected RWPE-1 cells. Moreover, EGFR-vIII changed the RWPE1 acinar morphogenesis. Further study showed that these effects of EGFR-vIII mutation may be related to down-regulation of E-cadherin and up-regulation of beta-catenin.
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Affiliation(s)
- M He
- Department of Urology, Mayo Clinic, Rochester, MN 55905 USA
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Shepard HM, Brdlik CM, Schreiber H. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family. J Clin Invest 2009; 118:3574-81. [PMID: 18982164 DOI: 10.1172/jci36049] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family-targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences.
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