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1
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Gao Q, Sun Z, Fang D. Integrins in human hepatocellular carcinoma tumorigenesis and therapy. Chin Med J (Engl) 2023; 136:253-268. [PMID: 36848180 PMCID: PMC10106235 DOI: 10.1097/cm9.0000000000002459] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Indexed: 03/01/2023] Open
Abstract
ABSTRACT Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.
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Affiliation(s)
- Qiong Gao
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China
| | - Zhaolin Sun
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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2
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Antitumor and apoptotic effects of new-generation platinum compounds on human leukemia cell lines HL-60 and K562. Biologia (Bratisl) 2021. [DOI: 10.1007/s11756-021-00930-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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3
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Wu P, Gao W, Su M, Nice EC, Zhang W, Lin J, Xie N. Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment. Front Cell Dev Biol 2021; 9:641469. [PMID: 33732706 PMCID: PMC7957022 DOI: 10.3389/fcell.2021.641469] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/05/2021] [Indexed: 02/05/2023] Open
Abstract
Cancer is a disease which frequently has a poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments frequently impedes the clinical outcomes. Besides the active resistance driven by genetic and epigenetic alterations in tumor cells, the tumor microenvironment (TME) has also been reported to be a crucial regulator in tumorigenesis, progression, and resistance. Here, we propose that the adaptive mechanisms of tumor resistance are closely connected with the TME rather than depending on non-cell-autonomous changes in response to clinical treatment. Although the comprehensive understanding of adaptive mechanisms driven by the TME need further investigation to fully elucidate the mechanisms of tumor therapeutic resistance, many clinical treatments targeting the TME have been successful. In this review, we report on recent advances concerning the molecular events and important factors involved in the TME, particularly focusing on the contributions of the TME to adaptive resistance, and provide insights into potential therapeutic methods or translational medicine targeting the TME to overcome resistance to therapy in clinical treatment.
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Affiliation(s)
- Peijie Wu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Wei Gao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Miao Su
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Edouard C. Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Wenhui Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jie Lin
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Na Xie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
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4
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Cao L, Wu Y, Wang X, Li X, Tan Z, Guan F. Role of Site-Specific Glycosylation in the I-Like Domain of Integrin β1 in Small Extracellular Vesicle-Mediated Malignant Behavior and FAK Activation. Int J Mol Sci 2021; 22:ijms22041770. [PMID: 33578954 PMCID: PMC7916680 DOI: 10.3390/ijms22041770] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/05/2021] [Accepted: 02/07/2021] [Indexed: 12/24/2022] Open
Abstract
Integrin β1 plays an essential role in the crosstalk between tumor cells and their microenvironment. Aberrant N-glycosylation of integrin β1 was documented to alter integrin β1 expression, dimerization, and biological function. However, the biological function of site-specific N-glycosylation of integrin β1 on extracellular vesicles is not fully understood. In this study, we mutated putative N-glycosylation sites in different domains of integrin β1. Removal of the N-glycosylation sites on the I-like domain of integrin β1 (termed the Δ4–6 β1 mutant) suppressed focal adhesion kinase (FAK) signaling, cell migration, and adhesion compared with other β1 mutants. Cell adhesion, migration, and activation of FAK were suppressed in recipient MCF7 cells co-cultured with Δ4–6 mutant cells and treated with small extracellular vesicles (sEVs) from Δ4–6 mutant cells. Notably, the wild-type and β1 mutant were both present in sEVs, and could be transferred to recipient cells via sEVs, resulting in changes of cell behavior. Our findings demonstrate the important roles of N-glycosylation of the I-like domain of integrin β1. Moreover, the vesicular Δ4–6 β1 mutant can regulate integrin-mediated functions in recipient cells via sEVs.
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5
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Petrov RA, Mefedova SR, Yamansarov EY, Maklakova SY, Grishin DA, Lopatukhina EV, Burenina OY, Lopukhov AV, Kovalev SV, Timchenko YV, Ondar EE, Ivanenkov YA, Evteev SA, Vaneev AN, Timoshenko RV, Klyachko NL, Erofeev AS, Gorelkin PV, Beloglazkina EK, Majouga AG. New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma. Mol Pharm 2020; 18:461-468. [PMID: 33264010 DOI: 10.1021/acs.molpharmaceut.0c00980] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21-75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20-35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.
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Affiliation(s)
- Rostislav A Petrov
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) of the Ufa Federal Research Centre, Oktyabrya Prospekt 71, Ufa 450054, Russian Federation
| | - Sofiia R Mefedova
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Emil Yu Yamansarov
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Svetlana Yu Maklakova
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Dmitrii A Grishin
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Elena V Lopatukhina
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Olga Y Burenina
- Skolkovo Institute of Science and Technology, 3 Nobel str., Skolkovo 143026, Russian Federation
| | - Anton V Lopukhov
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Sergey V Kovalev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Yury V Timchenko
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Evgenia E Ondar
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Yan A Ivanenkov
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) of the Ufa Federal Research Centre, Oktyabrya Prospekt 71, Ufa 450054, Russian Federation.,Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow 141700, Russian Federation
| | - Sergei A Evteev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Alexander N Vaneev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Roman V Timoshenko
- National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Natalia L Klyachko
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,Skolkovo Institute of Science and Technology, 3 Nobel str., Skolkovo 143026, Russian Federation
| | - Alexander S Erofeev
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Petr V Gorelkin
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation
| | - Elena K Beloglazkina
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation
| | - Alexander G Majouga
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.,National University of Science and Technology MISIS, 9 Leninskiy pr., Moscow 119049, Russian Federation.,Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russian Federation
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Dey S, Liu S, Factora TD, Taleb S, Riverahernandez P, Udari L, Zhong X, Wan J, Kota J. Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment. BMC Cancer 2020; 20:651. [PMID: 32660466 PMCID: PMC7359459 DOI: 10.1186/s12885-020-07135-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 07/02/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. METHODS In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing and control human PSCs (hPSCs). Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top miR-29a candidate targets in hPSCs transfected with miR-29a mimic or scramble control. RESULTS RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. CONCLUSIONS Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-cancer cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.
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Affiliation(s)
- Shatovisha Dey
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tricia D Factora
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Solaema Taleb
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Primavera Riverahernandez
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lata Udari
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xiaoling Zhong
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Janaiah Kota
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
- The Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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7
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Molina MF, Abdelnabi MN, Fabre T, Shoukry NH. Type 3 cytokines in liver fibrosis and liver cancer. Cytokine 2019; 124:154497. [PMID: 30097286 DOI: 10.1016/j.cyto.2018.07.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/23/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
The type 3 cytokines IL-17 and IL-22 play a crucial, well synchronized physiological role in wound healing and repairing tissue damage due to infections or injury at barrier surfaces. These cytokines act on epithelial cells to induce secretion of early immune mediators, recruitment of inflammatory cells to the site of injury, and to trigger tissue repair mechanisms. However, if the damage persists or if these cytokines are dysregulated, then they contribute to a number of inflammatory pathologies, autoimmune conditions and cancer. The liver is a multifunctional organ that plays an essential role in metabolism, detoxification, and immune surveillance. It is also exposed to a variety of pathogens, toxins and injuries. Over the past decade, IL-17 and IL-22 have been implicated in various aspects of liver inflammation. IL-17 is upregulated in chronic liver injury and associated with liver disease progression. In contrast, IL-22 was shown to be hepatoprotective during acute liver injury but exhibited inflammatory effects in other models. Furthermore, IL-22 and IL-17 are both associated with poor prognosis in liver cancer. Finally, the regulatory mechanisms governing the physiological versus the pathological role of these two cytokines during acute and chronic liver injury remain poorly understood. In this review, we will summarize the current state of knowledge about IL-17 and IL-22 in wound healing during acute and chronic liver injury, their contribution to pathogenesis, their regulation, and their role in the transition from advanced liver disease to liver cancer.
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Affiliation(s)
- Manuel Flores Molina
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Mohamed N Abdelnabi
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Thomas Fabre
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
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8
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Bechmann N, Ehrlich H, Eisenhofer G, Ehrlich A, Meschke S, Ziegler CG, Bornstein SR. Anti-Tumorigenic and Anti-Metastatic Activity of the Sponge-Derived Marine Drugs Aeroplysinin-1 and Isofistularin-3 against Pheochromocytoma In Vitro. Mar Drugs 2018; 16:E172. [PMID: 29783778 PMCID: PMC5983303 DOI: 10.3390/md16050172] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 05/12/2018] [Accepted: 05/15/2018] [Indexed: 01/07/2023] Open
Abstract
Over 10% of pheochromocytoma and paraganglioma (PPGL) patients have malignant disease at their first presentation in the clinic. Development of malignancy and the underlying molecular pathways in PPGLs are poorly understood and efficient treatment strategies are missing. Marine sponges provide a natural source of promising anti-tumorigenic and anti-metastatic agents. We evaluate the anti-tumorigenic and anti-metastatic potential of Aeroplysinin-1 and Isofistularin-3, two secondary metabolites isolated from the marine sponge Aplysina aerophoba, on pheochromocytoma cells. Aeroplysinin-1 diminished the number of proliferating cells and reduced spheroid growth significantly. Beside these anti-tumorigenic activity, Aeroplysinin-1 decreased the migration ability of the cells significantly (p = 0.01), whereas, the invasion capacity was not affected. Aeroplysinin-1 diminished the high adhesion capacity of the MTT cells to collagen (p < 0.001) and, furthermore, reduced the ability to form spheroids significantly. Western Blot and qRT-PCR analysis showed a downregulation of integrin β1 that might explain the lower adhesion and migration capacity after Aeroplysinin-1 treatment. Isofistularin-3 showed only a negligible influence on proliferative and pro-metastatic cell properties. These in vitro investigations show promise for the application of the sponge-derived marine drug, Aeroplysinin-1 as anti-tumorigenic and anti-metastatic agent against PPGLs for the first time.
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Affiliation(s)
- Nicole Bechmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
| | - Hermann Ehrlich
- Institute of Experimental Physics, TU Bergakademie Freiberg, Leipziger 23, 09599 Freiberg, Germany.
| | - Graeme Eisenhofer
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
- Department of Medicine III, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
| | - Andre Ehrlich
- BromMarin GmbH, Wernerstraße 1, 09599 Freiberg, Germany.
| | | | - Christian G Ziegler
- Department of Medicine III, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
| | - Stefan R Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
- Center for Regenerative Therapies Dresden, Technical University Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
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9
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Santos SN, Junqueira MS, Francisco G, Vilanova M, Magalhães A, Baruffi MD, Chammas R, Harris AL, Reis CA, Bernardes ES. O-glycan sialylation alters galectin-3 subcellular localization and decreases chemotherapy sensitivity in gastric cancer. Oncotarget 2016; 7:83570-83587. [PMID: 27835877 PMCID: PMC5347789 DOI: 10.18632/oncotarget.13192] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 10/21/2016] [Indexed: 12/12/2022] Open
Abstract
ST6GalNAc-I, the sialyltransferase responsible for sialyl-Tn (sTn) synthesis, has been previously reported to be positively associated with cancer aggressiveness. Here we describe a novel sTn-dependent mechanism for chemotherapeutic resistance. We show that sTn protects cancer cells against chemotherapeutic-induced cell death by decreasing the interaction of cell surface glycan receptors with galectin-3 and increasing its intracellular accumulation. Moreover, exogenously added galectin-3 potentiated the chemotherapeutics-induced cytotoxicity in sTn non-expressing cells, while sTn overexpressing cells were protected. We also found that the expression of sTn was associated with a reduction in galectin-3-binding sites in human gastric samples tumors. ST6GalNAc-I knockdown restored galectin-3-binding sites on the cell surface and chemotherapeutics sensibility. Our results clearly demonstrate that an interruption of O-glycans extension caused by ST6GalNAc-I enzymatic activity leads to tumor cells resistance to chemotherapeutic drugs, highlighting the need for the development of novel strategies to target galectin-3 and/or ST6GalNAc-I.
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MESH Headings
- Animals
- Antigens, Tumor-Associated, Carbohydrate/genetics
- Antigens, Tumor-Associated, Carbohydrate/metabolism
- Antineoplastic Agents/pharmacology
- Blood Proteins
- Cell Line, Tumor
- Cell Proliferation
- Cisplatin/pharmacology
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
- Galectin 3/metabolism
- Galectins
- Glycosylation
- Humans
- Mice, Inbred BALB C
- Mice, Nude
- Protein Processing, Post-Translational
- Protein Transport
- RNA Interference
- Sialyltransferases/genetics
- Sialyltransferases/metabolism
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Time Factors
- Transfection
- Tumor Burden
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Affiliation(s)
- Sofia N. Santos
- Department of Radiopharmacy, Nuclear Energy Research Institute, Radiopharmacy Center, São Paulo, Brazil
| | - Mara S. Junqueira
- Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil
| | - Guilherme Francisco
- Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil
| | - Manuel Vilanova
- I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
- IBMC Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal
- ICBAS-UP – Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Ana Magalhães
- I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
- Department of Glycobiology in Cancer, IPATIMUP - Institute of Molecular Pathology and Immunology from the University of Porto, Porto, Portugal
| | - Marcelo Dias Baruffi
- Department of Clinical, Toxicological and Bromatological Analysis, Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
| | - Roger Chammas
- Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao Paulo-ICESP, Brazil
| | - Adrian L. Harris
- Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Celso A. Reis
- I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
- ICBAS-UP – Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
- Department of Glycobiology in Cancer, IPATIMUP - Institute of Molecular Pathology and Immunology from the University of Porto, Porto, Portugal
- Department of Pathology and Oncology, Medical Faculty, University of Porto, Portugal
| | - Emerson S. Bernardes
- Department of Radiopharmacy, Nuclear Energy Research Institute, Radiopharmacy Center, São Paulo, Brazil
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10
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Faltas BM, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C, Rosenberg J, Mosquera JM, Robinson B, Elemento O, Sboner A, Beltran H, Demichelis F, Rubin MA. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet 2016; 48:1490-1499. [PMID: 27749842 PMCID: PMC5549141 DOI: 10.1038/ng.3692] [Citation(s) in RCA: 219] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Accepted: 09/09/2016] [Indexed: 02/08/2023]
Abstract
Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.
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Affiliation(s)
- Bishoy M. Faltas
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine. New York, NY
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. New York, NY
| | - Davide Prandi
- Centre for Integrative Biology, University of Trento. Trento, Italy
| | - Scott T. Tagawa
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine. New York, NY
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. New York, NY
| | - Ana M. Molina
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine. New York, NY
| | - David M. Nanus
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine. New York, NY
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. New York, NY
| | - Cora Sternberg
- Department of Medical Oncology, San Camillo and Forlanini Hospitals. Rome, Italy
| | - Jonathan Rosenberg
- Department of Medicine, Memorial Sloan Kettering Cancer Center. New York, NY
| | - Juan Miguel Mosquera
- Department of Pathology and Laboratory Medicine. Weill Cornell Medicine. New York, NY
| | - Brian Robinson
- Department of Pathology and Laboratory Medicine. Weill Cornell Medicine. New York, NY
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Department of Physiology and Biophysics. Weill Cornell Medicine. New York, NY
- Institute for Computational Biomedicine, Weill Cornell Medicine. New York, NY
| | - Andrea Sboner
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Department of Pathology and Laboratory Medicine. Weill Cornell Medicine. New York, NY
- Institute for Computational Biomedicine, Weill Cornell Medicine. New York, NY
| | - Himisha Beltran
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine. New York, NY
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. New York, NY
| | - Francesca Demichelis
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Centre for Integrative Biology, University of Trento. Trento, Italy
- Institute for Computational Biomedicine, Weill Cornell Medicine. New York, NY
| | - Mark A. Rubin
- Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. New York, NY
- Department of Pathology and Laboratory Medicine. Weill Cornell Medicine. New York, NY
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11
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El Khoury F, Corcos L, Durand S, Simon B, Le Jossic-Corcos C. Acquisition of anticancer drug resistance is partially associated with cancer stemness in human colon cancer cells. Int J Oncol 2016; 49:2558-2568. [PMID: 27748801 DOI: 10.3892/ijo.2016.3725] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 07/15/2016] [Indexed: 01/11/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most aggressive cancers worldwide. Several anticancer agents are available to treat CRC, but eventually cancer relapse occurs. One major cause of chemotherapy failure is the emergence of drug-resistant tumor cells, suspected to originate from the stem cell compartment. The aim of this study was to ask whether drug resistance was associated with the acquisition of stem cell-like properties. We isolated drug-resistant derivatives of two human CRC cell lines, HT29 and HCT116, using two anticancer drugs with distinct modes of action, oxaliplatin and docetaxel. HT29 cells resistant to oxaliplatin and both HT29 and HCT116 cells resistant to docetaxel were characterized for their expression of genes potentially involved in drug resistance, cell growth and cell division, and by surveying stem cell-like phenotypic traits, including marker genes, the ability to repair cell-wound and to form colonospheres. Among the genes involved in platinum or taxane resistance (MDR1, ABCG2, MRP2 or ATP7B), MDR1 was uniquely overexpressed in all the resistant cells. An increase in the cyclin-dependent kinase inhibitor p21, in cyclin D1 and in CD26, CD166 cancer stem cell markers, was noted in the resistant cells, together with a higher ability to form larger and more abundant colonospheres. However, many phenotypic traits were selectively altered in either HT29- or in HCT116-resistant cells. Expression of EPHB2, ITGβ-1 or Myc was specifically increased in the HT29-resistant cells, whereas only HCT116-resistant cells efficiently repaired cell- wounds. Taken together, our results show that human CRC cells selected for their resistance to anticancer drugs displayed a few stem cell characteristics, a small fraction of which was shared between cell lines. The occurrence of marked phenotypic differences between HT29- and HCT116-drug resistant cells indicates that the acquired resistance depends mostly on the parental cell characteristics, rather than on the drug type used.
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Affiliation(s)
- Flaria El Khoury
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
| | - Laurent Corcos
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
| | - Stéphanie Durand
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
| | - Brigitte Simon
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
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12
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Kim MY, Cho WD, Hong KP, Choi DB, Hong JW, Kim S, Moon YR, Son SM, Lee OJ, Lee HC, Song HG. Novel monoclonal antibody against beta 1 integrin enhances cisplatin efficacy in human lung adenocarcinoma cells. J Biomed Res 2016; 30:217-24. [PMID: 27533932 PMCID: PMC4885170 DOI: 10.7555/jbr.30.2016k0005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 02/24/2016] [Accepted: 02/25/2016] [Indexed: 11/03/2022] Open
Abstract
The use of anti-beta 1 integrin monoclonal antibody in lung cancer treatment has proven beneficial. Here, we developed a novel monoclonal antibody (mAb), called P5, by immunizing mice with human peripheral blood mononuclear cells (PBMC). Its anti-tumor effect is now being tested, in a clinical phase III trial, in combinatorial treatments with various chemical drugs. To confirm that P5 indeed binds to beta 1 integrin, cell lysates were immunoprecipitated with commercial anti-beta 1 integrin mAb (TS2/16) and immunoblotted against P5 to reveal a 140 kDa molecular weight band, as expected. Immunoprecipitation with P5 followed by LC/MS protein sequence analysis further verified P5 antigen to be beta 1 integrin. Cisplatin treatment upregulated cell surface expression of beta 1 integrin in A549 cells, while causing inhibition of cell growth. When cells were co-treated with different concentrations of P5 mAb, the cisplatin-mediated inhibitory effect was enhanced in a dose-dependent manner. Our findings show that a combinatorial treatment of P5 mAb and cisplatin in A549 cells resulted in a 30% increase in apoptosis, compared to baseline, and significantly more when compared to either the cisplatin or P5 alone group. The entire peptide sequences in CDR from variable region of Ig heavy and light chain gene for P5 mAb are also disclosed. Together, these results provide evidence of the beneficial effect of P5 mAb in combinatorial treatment of human lung adenocarcinoma.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Ok-Jun Lee
- Department of Pathology.,Research Institute, Chungbuk National University College of Medicine, Cheongju, 28644, Republic of Korea
| | - Ho-Chang Lee
- Department of Pathology.,Research Institute, Chungbuk National University College of Medicine, Cheongju, 28644, Republic of Korea
| | - Hyung Geun Song
- Department of Pathology.,Research Institute, Chungbuk National University College of Medicine, Cheongju, 28644, Republic of Korea.
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13
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Zhou F, Huang X, Zhang Z, Chen Y, Liu X, Xing J, He X. Functional polymorphisms of ITGB1 are associated with clinical outcome of Chinese patients with resected colorectal cancer. Cancer Chemother Pharmacol 2015; 75:1207-15. [PMID: 25894721 DOI: 10.1007/s00280-015-2745-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 04/02/2015] [Indexed: 01/05/2023]
Abstract
PURPOSE Integrin β1 (ITGB1) has been recognized to play a major role in tumor growth, invasion and metastasis. However, effects of single-nucleotide polymorphisms (SNPs) in ITGB1 gene on the prognosis of patients with colorectal cancer (CRC) have not been reported. METHODS A total of 372 patients with resected colorectal adenocarcinoma were enrolled in our study. Three functional SNPs (rs2230395, rs1187075 and rs1187076) in ITGB1 were selected and genotyped using the Sequenom iPLEX genotyping system. RESULTS We identified two SNPs (rs2230395 and rs1187075) in ITGB1 gene to be significantly associated with CRC overall survival (OS). Compared with the homozygous wild-type (AA) and heterozygous variant (AC), rs2230395 homozygous variant (CC) conferred a 1.55-fold (95 % CI 1.00-2.41, P = 0.049) increased risk of death. Similar result was obtained for homozygous variant (AA) in rs1187075 with a 1.62-fold (95 % CI 1.08-2.42, P = 0.020). In stratified analysis, this association in rs2230395 remained to be significant in patients receiving chemotherapy, but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival in subgroups stratified by rs2230395 and rs1187075 genotypes. We found that chemotherapy resulted in a significantly better OS in patients with the homozygous wild-type (WW) or heterozygous variant (WV) genotype in both rs2230395 and rs1187075 when compared with patients with homozygous variant (VV) genotype. CONCLUSIONS Our data suggest that ITGB1 SNPs might be a prognostic biomarker for CRC patients, especially in those receiving chemotherapy. Our findings warrant validation in larger independent populations.
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Affiliation(s)
- Feng Zhou
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, 169 West Changle Street, Xi'an, 710032, China
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14
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Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer. Oncogene 2015; 35:691-701. [PMID: 25639871 PMCID: PMC4522411 DOI: 10.1038/onc.2014.469] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 12/16/2014] [Accepted: 12/19/2014] [Indexed: 12/26/2022]
Abstract
The myc oncogene is overexpressed in almost half of all breast and ovarian cancers, but attempts at therapeutic interventions against myc have proven to be challenging. Myc regulates multiple biological processes, including the cell cycle, and as such is associated with cell proliferation and tumor progression. We identified a protein signature of high myc, low p27 and high phospho-Rb significantly correlated with poor patient survival in breast and ovarian cancers. Screening of a miRNA library by functional proteomics in multiple cell lines and integration of data from patient tumors revealed a panel of five microRNAs (miRNAs) (miR-124, miR-365, miR-34b*, miR-18a and miR-506) as potential tumor suppressors capable of reversing the p27/myc/phospho-Rb protein signature. Mechanistic studies revealed an RNA-activation function of miR-124 resulting in direct induction of p27 protein levels by binding to and inducing transcription on the p27 promoter region leading to a subsequent G1 arrest. Additionally, in vivo studies utilizing a xenograft model demonstrated that nanoparticle-mediated delivery of miR-124 could reduce tumor growth and sensitize cells to etoposide, suggesting a clinical application of miRNAs as therapeutics to target the functional effect of myc on tumor growth.
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15
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16
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Bai X, Wang J, Guo Y, Pan J, Yang Q, Zhang M, Li H, Zhang L, Ma J, Shi F, Shu W, Wang Y, Leng J. Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway. Sci Rep 2014; 4:6538. [PMID: 25289898 PMCID: PMC5377465 DOI: 10.1038/srep06538] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 09/05/2014] [Indexed: 02/07/2023] Open
Abstract
Prostaglandin E2 (PGE2) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased β1-integrin expression and cell migration; however, the mechanism remains unclear. PGE2 exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1–4). The present study investigated the effect of EP1 receptor activation on β1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT-PGE2 (EP1 agonist), which was suppressed by pretreatment with a β1-integrin polyclonal antibody. PGE2 increased β1-integrin expression by approximately 2-fold. EP1 receptor transfection or treatment with 17-PT-PGE2 mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated β1-integrin expression. 17-PT-PGE2 treatment induced PKC and NF-κB activation; PKC and NF-κB inhibitors suppressed 17-PT-PGE2-mediated β1-integrin expression. FoxC2, a β1-integrin transcription factor, was also upregulated by 17-PT-PGE2. NF-κB inhibitor suppressed 17-PT-PGE2-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and β1-integrin were all highly expressed in the HCC cases. This study suggested that PGE2 upregulates β1-integrin expression and cell migration in HCC cells by activating the PKC/NF-κB signaling pathway. Targeting PGE2/EP1/PKC/NF-κB/FoxC2/β1-integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer.
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Affiliation(s)
- Xiaoming Bai
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Jie Wang
- Department of Pathology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, P. R. China
| | - Yan Guo
- Institute of Pediatrics, Fourth Clinical Medical College, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Jinshun Pan
- The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Qinyi Yang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Min Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Hai Li
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Li Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Juan Ma
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Feng Shi
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Wei Shu
- Department of Periodontal, Institute of Stomatology, The Stomatological Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P. R. China
| | - Yipin Wang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Jing Leng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
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17
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Eke I, Cordes N. Focal adhesion signaling and therapy resistance in cancer. Semin Cancer Biol 2014; 31:65-75. [PMID: 25117005 DOI: 10.1016/j.semcancer.2014.07.009] [Citation(s) in RCA: 232] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/22/2014] [Accepted: 07/25/2014] [Indexed: 12/18/2022]
Abstract
Interlocking gene mutations, epigenetic alterations and microenvironmental features perpetuate tumor development, growth, infiltration and spread. Consequently, intrinsic and acquired therapy resistance arises and presents one of the major goals to solve in oncologic research today. Among the myriad of microenvironmental factors impacting on cancer cell resistance, cell adhesion to the extracellular matrix (ECM) has recently been identified as key determinant. Despite the differentiation between cell adhesion-mediated drug resistance (CAMDR) and cell adhesion-mediated radioresistance (CAMRR), the underlying mechanisms share great overlap in integrin and focal adhesion hub signaling and differ further downstream in the complexity of signaling networks between tumor entities. Intriguingly, cell adhesion to ECM is per se also essential for cancer cells similar to their normal counterparts. However, based on the overexpression of focal adhesion hub signaling receptors and proteins and a distinct addiction to particular integrin receptors, targeting of focal adhesion proteins has been shown to potently sensitize cancer cells to different treatment regimes including radiotherapy, chemotherapy and novel molecular therapeutics. In this review, we will give insight into the role of integrins in carcinogenesis, tumor progression and metastasis. Additionally, literature and data about the function of focal adhesion molecules including integrins, integrin-associated proteins and growth factor receptors in tumor cell resistance to radio- and chemotherapy will be elucidated and discussed.
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Affiliation(s)
- Iris Eke
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Dresden 01328, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Nils Cordes
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Dresden 01328, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden - Rossendorf, Dresden 01328, Germany.
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18
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Dittmer J, Leyh B. The impact of tumor stroma on drug response in breast cancer. Semin Cancer Biol 2014; 31:3-15. [PMID: 24912116 DOI: 10.1016/j.semcancer.2014.05.006] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 05/27/2014] [Accepted: 05/30/2014] [Indexed: 02/06/2023]
Abstract
In the last two decades the breast cancer mortality rate has steadily declined, in part, due to the availability of better treatment options. However, drug resistance still remains a major challenge. Resistance can be an inherent feature of breast cancer cells, but can also arise from the tumor microenvironment. This review aims to focus on the modulatory effect of the tumor microenvironment on the differing response of breast cancer subtypes to targeted drugs and chemotherapy.
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Affiliation(s)
- Jürgen Dittmer
- Clinic for Gynecology, University of Halle, Halle/Saale, Germany.
| | - Benjamin Leyh
- Clinic for Gynecology, University of Halle, Halle/Saale, Germany
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19
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Androgen receptor enhances cell adhesion and decreases cell migration via modulating β1-integrin-AKT signaling in hepatocellular carcinoma cells. Cancer Lett 2014; 351:64-71. [PMID: 24944078 DOI: 10.1016/j.canlet.2014.05.017] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 03/24/2014] [Accepted: 05/01/2014] [Indexed: 12/21/2022]
Abstract
The androgen receptor (AR) has been shown to promote the initiation and development of hepatocellular carcinoma (HCC) during the early stage of the disease process and to suppress HCC cell invasion during the later stages of the disease. The mechanisms governing these dual yet opposite roles have yet to be elucidated. Using carcinogen-induced HCC in vivo mouse models and the in vitro human HCC cell line SKhep1, we found that knockout of AR in primary HCC cells led to a decrease in HCC cell focal adhesion capacity compared to cells from wildtype mice. Similar results were obtained after adding functional AR into human HCC SKhep1 cells. Further analysis revealed that the role AR plays in adhesion of HCC cells is governed, at least in part, by its ability to up-regulate β1-integrin and activate the PI3K/AKT pathway. We also found that AR-β1-integrin-mediated cell adhesion suppresses cell migration. Those findings indicate that the AR-β1-integrin-PI3K/AKT signaling pathway might play a role in the bimodal function of AR on cell adhesion and migration at the cellular level.
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20
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Lovitt CJ, Shelper TB, Avery VM. Advanced cell culture techniques for cancer drug discovery. BIOLOGY 2014; 3:345-67. [PMID: 24887773 PMCID: PMC4085612 DOI: 10.3390/biology3020345] [Citation(s) in RCA: 173] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/16/2014] [Accepted: 05/22/2014] [Indexed: 12/21/2022]
Abstract
Human cancer cell lines are an integral part of drug discovery practices. However, modeling the complexity of cancer utilizing these cell lines on standard plastic substrata, does not accurately represent the tumor microenvironment. Research into developing advanced tumor cell culture models in a three-dimensional (3D) architecture that more prescisely characterizes the disease state have been undertaken by a number of laboratories around the world. These 3D cell culture models are particularly beneficial for investigating mechanistic processes and drug resistance in tumor cells. In addition, a range of molecular mechanisms deconstructed by studying cancer cells in 3D models suggest that tumor cells cultured in two-dimensional monolayer conditions do not respond to cancer therapeutics/compounds in a similar manner. Recent studies have demonstrated the potential of utilizing 3D cell culture models in drug discovery programs; however, it is evident that further research is required for the development of more complex models that incorporate the majority of the cellular and physical properties of a tumor.
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Affiliation(s)
- Carrie J Lovitt
- Discovery Biology, Griffith University, N27, Don Young Road, Nathan, Queensland, 4111, Australia.
| | - Todd B Shelper
- Discovery Biology, Griffith University, N27, Don Young Road, Nathan, Queensland, 4111, Australia.
| | - Vicky M Avery
- Discovery Biology, Griffith University, N27, Don Young Road, Nathan, Queensland, 4111, Australia.
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21
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Lee YA, Friedman SL. Reversal, maintenance or progression: what happens to the liver after a virologic cure of hepatitis C? Antiviral Res 2014; 107:23-30. [PMID: 24726738 DOI: 10.1016/j.antiviral.2014.03.012] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 03/17/2014] [Accepted: 03/18/2014] [Indexed: 02/07/2023]
Abstract
A sustained virological response (SVR) from HCV (synonymous with virological cure) leads to decreased mortality, morbidity and improved quality of life, as well as a reduced incidence of liver disease progression, including liver failure, cirrhosis and hepatocellular carcinoma. Large clinical trials comparing pre- and post-treatment liver biopsies demonstrate improvements in inflammation as well as fibrosis score following SVR. However, a small subset of patients display persistent hepatic inflammation and/or progress to cirrhosis despite SVR. In addition to conferring a risk of fibrosis progression, advanced fibrosis pre-treatment is a major risk factor for post-SVR hepatocellular carcinoma. In this review, we discuss the mechanisms of fibrosis regression uncovered using experimental fibrosis models and highlight potential mechanisms in those few patients with fibrosis progression despite SVR. We also introduce current concepts of fibrosis-dependent tumorigenesis post-SVR in patients with advanced disease. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Youngmin A Lee
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA.
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22
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Bai X, Yang Q, Shu W, Wang J, Zhang L, Ma J, Xia S, Zhang M, Cheng S, Wang Y, Leng J. Prostaglandin E2 upregulates β1 integrin expression via the E prostanoid 1 receptor/nuclear factor κ-light-chain-enhancer of activated B cells pathway in non-small-cell lung cancer cells. Mol Med Rep 2014; 9:1729-36. [PMID: 24584670 DOI: 10.3892/mmr.2014.2000] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 02/13/2014] [Indexed: 11/06/2022] Open
Abstract
The prostaglandin E2 (PGE2) E prostanoid (EP)1 receptor shown to be associated with lung cancer cell invasion. However, the mechanism of EP1 receptor-mediated cell migration remains to be elucidated. β1 integrin is an essential regulator of the tumorigenic properties of non-small-cell lung carcinoma (NSCLC) cells. To date, little is known regarding the association between the EP1 receptor and β1 integrin expression. The present study investigated the effect of EP1 receptor activation on β1 integrin expression and cell migration in NSCLC cells. A total of 34 patients with clinical diagnosis of NSCLC and 10 patients with benign disease were recruited for the present study. The expression levels of the EP1 receptor and β1 integrin expression were studied in resected lung tissue using immunohistochemistry. A statistical analysis was performed using Stata se12.0 software. The effects of PGE2, EP1 agonist 17-phenyl trinor-PGE2 (17-PT-PGE2) and the nuclear factor κ-B (NF-κB) inhibitor on β1 integrin expression were investigated on A549 cells. The expression of β1 integrin and the phosphorylation of NF-κB‑p65 Ser536 was investigated by western blot analysis. Cell migration was assessed by a transwell assay. The results demonstrated that β1 integrin and EP1 receptor expression exhibited a positive correlation of evident significance in the 44 samples. The in vitro migration assay revealed that cell migration was increased by 30% when the cells were treated with 5 µM 17-PT-PGE2 and that the pre-treatment of β1 integrin monoclonal antibody inhibited 17-PT-PGE2‑mediated cell migration completely. PGE2 and 17-PT-PGE2 treatment increased β1 integrin expression. RNA interference against the EP1 receptor blocked the PGE2-mediated β1 integrin expression in A549 cells. Treatment with 17-PT-PGE2 induced NF-κB activation, and the selective NF-κB inhibitor pyrrolidinedithiocarbamate inhibited 17-PT-PGE2-mediated β1 integrin expression. In conclusion, the present study indicated that the PGE2 EP1 receptor regulates β1 integrin expression and cell migration in NSCLC cells by activating the NF-κB signaling pathway. Targeting the PGE2/EP1/β1 integrin signaling pathway may aid in the development of new therapeutic strategies for the prevention and treatment of this type of cancer.
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Affiliation(s)
- Xiaoming Bai
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Qinyi Yang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Wei Shu
- Department of Periodontal, Institute of Stomatology, The Stomatological Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jie Wang
- Department of Pathology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Li Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Juan Ma
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Shukai Xia
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Min Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Shanyu Cheng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yipin Wang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jing Leng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Ng L, Tung-Ping Poon R, Yau S, Chow A, Lam C, Li HS, Chung-Cheung Yau T, Law WL, Pang R. Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion. Hepatology 2013; 58:667-79. [PMID: 23504997 DOI: 10.1002/hep.26396] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 03/07/2013] [Indexed: 12/07/2022]
Abstract
UNLABELLED Early reports suggested that actopaxin, a member of the focal adhesion proteins, regulates cell migration. Here we investigated whether actopaxin is involved in hepatocellular carcinoma (HCC) progression and metastasis. We examined actopaxin expression in human HCC samples using immunohistochemistry and western blotting. The functional and molecular effect of actopaxin was studied in vitro by overexpression in a nonmetastatic HCC cell line, as well as repression in a metastatic cell line. The in vivo effect of actopaxin repression was studied in nonobese diabetic and severe combined immunodeficient mice. We found that actopaxin was frequently overexpressed in human HCC patients and its overexpression positively correlated with tumor size, stage, and metastasis. Actopaxin expression also correlated with the metastatic potential of HCC cell lines. Actopaxin overexpression induced the invasion and migration ability of nonmetastatic HCC cells, whereas down-regulation of actopaxin reverted the invasive phenotypes and metastatic potential of metastatic HCC cells through regulating the protein expression of certain focal adhesion proteins including ILK, PINCH, paxillin, and cdc42, as well as regulating the epithelial-mesenchymal transition pathway. Furthermore, there was a close association between actopaxin and CD29. HCC cells with stronger CD29 expression showed a higher actopaxin level, whereas actopaxin repression attenuated CD29 activity. Finally, actopaxin down-regulation enhanced the chemosensitivity of HCC cells towards oxaliplatin treatment by way of a collective result of suppression of survivin protein, β-catenin, and mammalian target of rapamycin pathways and up-regulation of p53. CONCLUSION This study provides concrete evidence of a significant role of actopaxin in HCC progression and metastasis, by way of regulation of cell invasiveness and motility, an epithelial-mesenchymal transition process, and chemosensitivity to cytotoxic drugs.
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Affiliation(s)
- Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 2012; 56:769-75. [PMID: 22378017 PMCID: PMC4087159 DOI: 10.1002/hep.25670] [Citation(s) in RCA: 320] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 02/11/2012] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a rising worldwide cause of cancer mortality, making the elucidation of its underlying mechanisms an urgent priority. The liver is unique in its response to injury, simultaneously undergoing regeneration and fibrosis. HCC occurs in the context of these two divergent responses, leading to distinctive pathways of carcinogenesis. In this review we highlight pathways of liver tumorigenesis that depend on, or are enhanced by, fibrosis. Activated hepatic stellate cells drive fibrogenesis, changing the composition of the extracellular matrix. Matrix quantity and stiffness also increase, providing a reservoir for bound growth factors. In addition to promoting angiogenesis, these factors may enhance the survival of both preneoplastic hepatocytes and activated hepatic stellate cells. Fibrotic changes also modulate the activity of inflammatory cells in the liver, reducing the activity of natural killer and natural killer T cells that normally contribute to tumor surveillance. These pathways synergize with inflammatory signals, including telomerase reactivation and reactive oxygen species release, ultimately resulting in cancer. Clarifying fibrosis-dependent tumorigenic mechanisms will help rationalize antifibrotic therapies as a strategy to prevent and treat HCC.
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Affiliation(s)
- David Y Zhang
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA
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25
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Correia AL, Bissell MJ. The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist Updat 2012; 15:39-49. [PMID: 22335920 DOI: 10.1016/j.drup.2012.01.006] [Citation(s) in RCA: 320] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The emergence of clinical drug resistance is still one of the most challenging factors in cancer treatment effectiveness. Until more recently, the assumption has been that random genetic lesions are sufficient to explain the progression of malignancy and escape from chemotherapy. Here we propose an additional perspective, one in which the tumor cells despite the malignant genome could find a microenvironment either within the tumor or as a dormant cell to remain polar and blend into an organized context. Targeting this dynamic interplay could be considered a new avenue to prevent therapeutic resistance, and may even provide a promising effective cancer treatment.
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Affiliation(s)
- Ana Luísa Correia
- Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS 977, Berkeley, CA 94720, USA
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26
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Jinturkar KA, Anish C, Kumar MK, Bagchi T, Panda AK, Misra AR. Liposomal formulations of Etoposide and Docetaxel for p53 mediated enhanced cytotoxicity in lung cancer cell lines. Biomaterials 2011; 33:2492-507. [PMID: 22200537 DOI: 10.1016/j.biomaterials.2011.11.067] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2011] [Accepted: 11/25/2011] [Indexed: 01/09/2023]
Abstract
The objective of present investigation was to develop and assess comparative enhancement in cytotoxicity of liposomal Etoposide and Docetaxel in non-small cell lung cancer cell lines after pre-treatment and co-administration of p53 tumor suppressor gene and to assess direct lung targeting of optimized formulations by dry powder inhaler technology. Cationic liposomes with and without drug were prepared and allowed to form p53-lipoplex for undertaking cytotoxicity studies in H-1299 (p53 null) and A-549 (p53 wt) cell lines. The optimized lipoplexes showed average size of 200-350 nm, zeta potential of 25-32 mV and sustained drug release up to 16-24 h. The developed liposomes and lipoplexes showed significant intracellular uptake and demonstrated enhanced cytotoxicity of 13-28 % after p53-drug co-administration and 41-63 % after p53 pre-treatment. The p53 mediated enhanced cytotoxicity by increased apoptosis and necrosis was also confirmed using Annexin V - FITC assay. The increased apoptosis suggested restored p53 function and reduced anti-apoptotic drug resistance theirby causing cell sensitization and synergism towards cytotoxicity. The studies conducted above demonstrated significant cell chemo-sensitization after p53 pre-treatment followed by Etoposide/Docetaxel liposomes administration than p53-Etoposide or p53-Docetaxel lipoplex co-administration; more significantly in Docetaxel and in H 1299 cell line. All the formulations when developed as dry powder inhalers showed significant in vitro lung deposition pattern in cascade impactor with fine particle faction of 33-37%. The study opens up a new strategy to treat lung cancer especially in cases of drug resistance. Moreover direct delivery to lung may provide an important role in complete remission of the disease due to target specificity.
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Affiliation(s)
- Kaustubh A Jinturkar
- Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Post Box No.: 51, Kalabhavan, Vadodara 390 001, Gujarat state, India
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27
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Ozaki I, Hamajima H, Matsuhashi S, Mizuta T. Regulation of TGF-β1-Induced Pro-Apoptotic Signaling by Growth Factor Receptors and Extracellular Matrix Receptor Integrins in the Liver. Front Physiol 2011; 2:78. [PMID: 22028694 PMCID: PMC3199809 DOI: 10.3389/fphys.2011.00078] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Accepted: 10/11/2011] [Indexed: 01/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) often arises from chronically diseased livers. Persistent liver inflammation causes the accumulation of excessive extracellular matrix (ECM) proteins and impairs the liver function, finally leading to the development of HCC. A pleiotropic cytokine, transforming growth factor (TGF)-β1, plays critical roles throughout the process of fibrogenesis and hepatocarcinogenesis. In the liver, TGF-β1 inhibits the proliferation of hepatocytes and stimulates the production of ECM from hepatic stellate cells (HSCs) to maintain tissue homeostasis. During disease progression, both growth factors/cytokines and the ECM alter the TGF-β1 signals by modifying the phosphorylation of Smad proteins at their C-terminal and linker regions. TGF-β1 stimulates the expression of integrins, cellular receptors for ECM, along with an increase in ECM accumulation. The activation of integrins by the ECM modulates the response to TGF-β1 in hepatic cells, resulting in their resistance to TGF-β1-induced growth suppression in hepatocytes and the sustained production of ECM proteins in activated HSCs/myofibroblasts. Both growth factor receptors and integrins modify the expression and/or functions of the downstream effectors of TGF-β1, resulting in the escape of hepatocytes from TGF-β1-induced apoptosis. Recent studies have revealed that the alterations of Smad phosphorylation that occur as the results of the crosstalk between TGF-β1, growth factors and integrins could change the nature of TGF-β1 signals from tumor suppression to promotion. Therefore, the modification of Smad phosphorylation could be an attractive target for the prevention and/or treatment of HCC.
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Affiliation(s)
- Iwata Ozaki
- Saga Medical School, Health Administration Center Saga, Japan
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28
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Zhang CY, Hu P, Fu D, Wu W, Jia CY, Zhu XC, Wu XZ. 3'-Sulfo-Le(x) is important for regulation of integrin subunit alphaV. Biochemistry 2010; 49:7811-20. [PMID: 20695481 DOI: 10.1021/bi101040k] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Carbohydrate structures with a 3'-sulfo betaGal linkage, such as 3'-sulfo-Le(x), can be synthesized by Gal:3-O-sulfotransferase-2 (Gal3ST-2) catalysis, but little is known about their roles in many biological processes. To investigate the role of Gal3ST-2 and its product 3'-sulfo-Le(x), we depleted Gal3ST-2 via siRNA and added exogenous Lewis-x trisaccharide 3'-sulfate sodium salt in human SMMC7721 hepatoma cells. After siRNA transfection, a striking morphological change in SMMC7721 hepatoma cells from polygon to shuttle shape and a significant decrease in the level of adhesion to sL-selectin, HUVEC, fibronectin, vitronectin, and fibrinogen were observed. The expression of integrin subunit alphaV was markedly downregulated, and 3'-sulfated subunit alphaV almost disappeared in the transfectants. The level of cell surface integrin alphaVbeta3 was reduced simultaneously, although total subunit beta3 underwent almost no change. After treatment with exogenous Lewis-x 3'-sulfate, cellular integrin subunit alphaV was upregulated and the level of cell surface integrin alphaVbeta3 was elevated. Interestingly, knockdown of Gal3ST-2 expression effectively inhibited cell proliferation, and the result was significantly correlated with the decrease in the levels of ILK, phosphorylated AKT, and ERK. On the other hand, treatment with Lewis-x trisaccharide 3'-sulfate sodium salt greatly upregulated the phosphorylation of AKT and ERK. Our results also indicated that downregulation of Gal3ST-2 via siRNA transfection was associated with the decrease in the level of expression of anti-apoptotic protein, Bcl-2, with a consequent decrease in the ratios for Bcl-2 to Bax. By exposure to Lewis-x trisaccharide 3'-sulfate sodium salt, the apoptotic response of cells was inhibited. Therefore, Gal3ST-2 and its product, 3'-sulfo-Le(x), were involved in regulation of integrin subunit alphaV and might be associated with cancer cell regulation.
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Affiliation(s)
- Chun-Yi Zhang
- Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China
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Caccia D, Miccichè F, Cassinelli G, Mondellini P, Casalini P, Bongarzone I. Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET/PTC1-expressing cell line. Mol Cancer 2010; 9:278. [PMID: 20955590 PMCID: PMC2967544 DOI: 10.1186/1476-4598-9-278] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Accepted: 10/18/2010] [Indexed: 11/15/2022] Open
Abstract
Background TPC-1 is a papillary thyroid carcinoma (PTC)-derived cell line that spontaneously expresses the oncogene RET/PTC1. TPC-1 treated with the RET/PTC1 inhibitor RPI-1 displayed a cytostatic and reversible inhibition of cell proliferation and a strong activation of focal adhesion kinase (FAK). As dasatinib inhibition of Src results in reduction of FAK activation, we evaluated the effects of TPC-1 treatment with dasatinib in combination with RPI-1. Results Dasatinib (100 nM) strongly reduced TPC-1 proliferation and induced marked changes in TPC-1 morphology. Cells appeared smaller and more contracted, with decreased cell spreading, due to the inhibition of phosphorylation of important cytoskeletal proteins (p130CAS, Crk, and paxillin) by dasatinib. The combination of RPI-1 with dasatinib demonstrated enhanced effects on cell proliferation (more than 80% reduction) and on the phosphotyrosine protein profile. In particular, RPI-1 reduced the phosphorylation of RET, MET, DCDB2, CTND1, and PLCγ, while dasatinib acted on the phosphorylation of EGFR, EPHA2, and DOK1. Moreover, dasatinib completely abrogated the phosphorylation of FAK at all tyrosine sites (Y576, Y577, Y861, Y925) with the exception of the autoactivation site (Y397). Notably, the pharmacological treatments induced an overexpression of integrin β1 (ITB1) that was correlated with a mild enhancement in phosphorylation of ERK1/2 and STAT3, known for their roles in prevention of apoptosis and in increase of proliferation and survival. A reduction in Akt, p38 and JNK1/2 activation was observed. Conclusions All data demonstrate that the combination of the two drugs effectively reduced cell proliferation (by more than 80%), significantly decreased Tyr phosphorylation of almost all phosphorylable proteins, and altered the morphology of the cells, supporting high cytostatic effects. Following the combined treatment, cell survival pathways appeared to be mediated by STAT3 and ERK activities resulting from integrin clustering and FAK autophosphorylation. EphA2 may also contribute, at least in part, to integrin and FAK activation. In conclusion, these data implicate ITB1 and EphA2 as promising therapeutic targets in PTC.
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Affiliation(s)
- Dario Caccia
- Department of Experimental Oncology and Molecular Medicine, Proteomics Laboratory, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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30
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Affiliation(s)
- Nils Cordes
- OncoRay – Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Catherine C. Park
- Department of Radiation Oncology, University of California, San Francisco, California, USA
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31
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Lee SK, Kim MH, Cheong JY, Cho SW, Yang SJ, Kwack K. Integrin alpha V polymorphisms and haplotypes in a Korean population are associated with susceptibility to chronic hepatitis and hepatocellular carcinoma. Liver Int 2009; 29:187-95. [PMID: 18694400 DOI: 10.1111/j.1478-3231.2008.01843.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Integrins are cell surface receptors for extracellular matrix (ECM) proteins that initiate signalling pathways that modulate proliferation, survival, invasion or metastasis. Consequently, integrins are potential targets for the treatment of cancer. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in integrin alpha(V) (ITGAV) in a Korean population were associated with chronic hepatitis B virus (HBV) infection and HBV-infected hepatocellular carcinoma (HCC). PATIENTS AND METHODS Thirteen ITGAV SNPs in 111 cases of chronic HBV infection, 86 cases of HBV-infected HCC and 107 cases of acute self-limited HBV infection were genotyped using Illumina's Sentrix array matrix (SAM) chip. RESULTS The ITGAV intron SNPs rs9333289 and rs11685758, the 3'-untranslated region SNP rs1839123 and haplotype 3 (T-T-A) were associated with enhanced susceptibility to HBV-infected HCC (OR=1.75-2.42; P=0.02-0.05), while the intron SNP rs2290083 was associated with both chronic infection and HBV-infected HCC (OR=1.73-2.01; P=0.01-0.04). In addition, both rs2290083 and ht1 (C-C-G) were associated with the age at which chronic infection occurred, as determined by Cox relative hazard analysis (RH=1.39-1.62, P=0.04-0.01) CONCLUSION ITGAV SNPs and haplotypes may be genetic factors that increase the susceptibility of Koreans to chronic HBV infection and HBV-infected HCC.
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Affiliation(s)
- Seung Ku Lee
- Medical Genomics Laboratory, Graduate School of Life Science and Biotechnology, Pochon CHA University, SeongNam, Korea
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Studies indicate that the development of HCC is related to signal transduction of Ras-MAPK.P38MAPK, an important member of the family of mitogen-activated protein kinases. P38MAPK participates in cell proliferation, apoptosis and differentiation and plays a key role in cell apoptosis. P38MAPK is closely related with carcinogenesis, rapid generation and infinite growth of liver cancer and plays a role in the occurrence and development of liver cancer induced by organics, HBV and HCV. Drugs exert their anti-tumor effects through p38MAPK which also takes part in the formation of drug resistance to HCC. This paper reviews the advances in studies on p38MAPK-related HCC.
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Takeda I, Maruya SI, Shirasaki T, Mizukami H, Takahata T, Myers JN, Kakehata S, Yagihashi S, Shinkawa H. Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci 2007; 98:890-9. [PMID: 17428261 PMCID: PMC11159053 DOI: 10.1111/j.1349-7006.2007.00471.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, also called statins, are commonly used as lipid-lowering drugs that inhibit cholesterol biosynthesis. An anticancer effect, as a pleiotropic function of certain statins, has been hypothesized. In the present study, we investigated the effect of simvastatin, one of the natural statins, on cell proliferation, cell cycle, invasive activity, and molecular expressions associated with cell-extracellular matrix adhesion, signal transduction, and DNA synthesis in Tu167 and JMAR cells from head and neck squamous cell carcinoma. The addition of simvastatin resulted in a dose-dependent inhibition of cell growth and migration into the extracellular matrix. Considerable morphological changes occurred after treatment with simvastatin, demonstrating loss of cell adhesion and disruption of actin filaments in cytoplasm. The inhibitory effect of simvastatin on cell proliferation seemed to be associated with cell cycle arrest and increased expression of p21, p27, and activated caspase-3. The expression of beta1-integrin, a counter adhesion for the extracellular matrix, phosphorylated FAK, and phosphorylated ERK was decreased by treatment with simvastatin. The proapoptotic effect of simvastatin was inhibited by treatment with mevalonate. cDNA microarray assay demonstrated that molecular changes resulting from treatment with simvastatin included the up-regulation of cell cycle regulators and apoptosis-inducing factors and the down-regulation of integrin-associated molecules and cell proliferation markers. Of down-regulated genes induced by simvastatin treatment, a significant depletion of thymidylate synthase was confirmed using western blot analysis. These results imply that simvastatin has the potential to be effective for the prevention of the growth and metastasis of cancer cells.
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Affiliation(s)
- Ikuko Takeda
- Department of Otolaryngology, Hirosaki University school of Medicine, Hirosaki, Japan
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Hehlgans S, Haase M, Cordes N. Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta Rev Cancer 2006; 1775:163-80. [PMID: 17084981 DOI: 10.1016/j.bbcan.2006.09.001] [Citation(s) in RCA: 164] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2006] [Revised: 09/26/2006] [Accepted: 09/28/2006] [Indexed: 01/13/2023]
Abstract
Integrin-associated signalling renders cells more resistant to genotoxic anti-cancer agents like ionizing radiation and chemotherapeutic substances, a phenomenon termed cell adhesion-mediated radioresistance/drug resistance (CAM-RR, CAM-DR). Integrins are heterodimeric cell-surface molecules that on one side link the actin cytoskeleton to the cell membrane and on the other side mediate cell-matrix interactions. In addition to their structural functions, integrins mediate signalling from the extracellular space into the cell through integrin-associated signalling and adaptor molecules such as FAK (focal adhesion kinase), ILK (integrin-linked kinase), PINCH (particularly interesting new cysteine-histidine rich protein) and Nck2 (non-catalytic (region of) tyrosine kinase adaptor protein 2). Via these molecules, integrin signalling tightly and cooperatively interacts with receptor tyrosine kinase signalling to regulate survival, proliferation and cell shape as well as polarity, adhesion, migration and differentiation. In tumour cells of diverse origin like breast, colon or skin, the function and regulation of these molecules is partly disturbed and thus might contribute to the malignant phenotype and pre-existent and acquired multidrug resistance. These issues as well as a variety of therapeutic options envisioned to influence tumour cell growth, metastasis and resistance, including kinase inhibitors, anti-integrin antibodies or RNA interference, will be summarized and discussed in this review.
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Affiliation(s)
- Stephanie Hehlgans
- OncoRay, Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstrasse 74/PF 86, 01307 Dresden, Germany
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35
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Cordes N. Integrin-mediated cell–matrix interactions for prosurvival and antiapoptotic signaling after genotoxic injury. Cancer Lett 2006; 242:11-9. [PMID: 16448744 DOI: 10.1016/j.canlet.2005.12.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Revised: 11/22/2005] [Accepted: 12/04/2005] [Indexed: 01/10/2023]
Abstract
Interactions of cells with their microenvironment modify the cellular sensitivity of normal and tumor cells for radiation- and drug-induced genotoxic injury. The preexistent or acquired cellular resistance against such agents aggravates anticancer therapies and, therefore, complicates the recovery of patients. Recently, integrin-mediated adhesion was shown to improve cell survival of both normal and cancer cells following DNA damage. Here, I will discuss the role of integrins and integrin-mediated signaling cascades in the survival or death response upon genotoxic stress. Detailed knowledge of the responsible molecular processes might provide implications for putative therapies targeting integrins or integrin-associated molecules to achieve an optimization of anticancer treatments.
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Affiliation(s)
- Nils Cordes
- OncoRay-Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden,Fetscherstrasse 74/PF 86, 01307 Dresden, Germany.
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Jo JY, de Mejia EG, Lila MA. Cytotoxicity of bioactive polymeric fractions from grape cell culture on human hepatocellular carcinoma, murine leukemia and non-cancerous PK15 kidney cells. Food Chem Toxicol 2006; 44:1758-67. [PMID: 16828532 DOI: 10.1016/j.fct.2006.05.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2005] [Revised: 05/12/2006] [Accepted: 05/25/2006] [Indexed: 01/16/2023]
Abstract
Previously, we isolated two fractions (TP-4 and TP-6) from grape cell culture that were potent catalytic inhibitors in a human DNA topoisomerase II assay for cancer chemoprevention. The objectives of this study were to further assess cytotoxicity of these fractions on cancerous and non-cancerous cells, and to subfractionate and characterize the composition of TP-6, a fraction that was selectively cytotoxic to carcinoma cell lines. Both TP-4 and TP-6 provided significant cytotoxicity to L1210 mouse leukemia cells. Only TP-6, a procyanidin-rich fraction, significantly reduced viability in HepG2 human liver cancer cells, yet unlike resveratrol, caused no cytotoxicity to non-cancerous PK15 pig kidney cells. After further subfractionation of TP-6 (maximal toxicity = 67.2%; ED(50) = 50.5 microM), the cytotoxicity of subfractions on HepG2 cells was TP-6-5 (maximal toxicity=71.8%; ED(50) = 14.1 microM), TP-6-6 (maximal toxicity=64.3%; ED(50) = 67.0 microM), and TP-6-4 (maximal toxicity = 27.6%; ED(50) = 118.0 microM) in descending order. LC-ESI/MS data suggested that cytotoxicity of these procyanidin mixtures to HepG2 cells was proportional to the degree of polymerization. Because TP-6 and its subfractions were selectively cytotoxic to cancerous cell lines tested, they warrant further investigation as potential natural anticancer agents.
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Affiliation(s)
- Jeong-Youn Jo
- Department of Natural Resources and Environmental Sciences, 1021 Plant Sciences Laboratory MC 634, University of Illinois at Urbana-Champaign, 1201 S. Dorner Drive, 61801, USA
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Hess F, Estrugo D, Fischer A, Belka C, Cordes N. Integrin-linked kinase interacts with caspase-9 and -8 in an adhesion-dependent manner for promoting radiation-induced apoptosis in human leukemia cells. Oncogene 2006; 26:1372-84. [PMID: 16936772 DOI: 10.1038/sj.onc.1209947] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Integrin-mediated adhesion of leukemia cells to extracellular matrix proteins reduces apoptosis following radiation-induced genotoxic injury. To evaluate the role of integrin-linked kinase (ILK) in this process, HL60 human acute promyelocytic leukemia cells were stably transfected with ILK wild-type or kinase-hyperactive overexpression vectors. Suspension or fibronectin (FN) adhesion cultures were irradiated with X-rays and processed for measurement of apoptosis, mitochondrial transmembrane potential and caspase activation. Adhesion to FN pronouncedly reduced radiation-induced apoptosis of HL60 cells and vector controls. Intriguingly, overexpressed ILK enhanced apoptosis after irradiation by combined activation of caspase-3 through caspase-8 and -9 in irradiated FN cultures. Irradiation of ILK suspension cultures lacked caspase-8 activation, but showed serial cleavage of caspase-9, -3 and poly (ADP-ribose) polymerase. These findings further characterize the cell death-promoting function of ILK in DNA-damaged cells. Moreover, ILK might represent a potential therapeutic target for innovative chemo- and radiooncological approaches in hematological malignancies.
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Affiliation(s)
- F Hess
- Bundeswehr Institute of Radiobiology, Munich, Germany
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Abstract
Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is often diagnosed at an advanced stage when most potentially curative therapies such as resection, transplantation or percutaneous and transarterial interventions are of limited efficacy. The fact that HCC is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy, leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver disease. However, in spite of this heterogeneity recent insights into the biology of HCC suggest that certain signaling pathways and molecular alterations are likely to play essential roles in HCC development by promoting cell growth and survival. The identification of such mechanisms may open new avenues for the prevention and treatment of HCC through the development of targeted therapies. In this review we will describe the new potential therapeutic targets and clinical developments that have emerged from progress in the knowledge of HCC biology, In addition, recent advances in gene therapy and combined cell and gene therapy, together with new radiotherapy techniques and immunotherapy in patients with HCC will be discussed.
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Affiliation(s)
- M A Avila
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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39
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Abstract
The composition of the extracellular matrix in tumors is vastly different from that found in the normal tissue counterparts. As the extracellular matrix can signal to cells via integrin binding and activation, which is known to modulate cell proliferation, survival and migration, it may influence the response of both tumor and endothelial cells to anticancer therapies. Certain tumor-associated extracellular matrix proteins have been shown to confer resistance to chemotherapeutic drugs, radiation and anti-angiogenic factors. The current literature regarding this phenomenon and the potential therapeutic modalities to overcome extracellular matrix-induced resistance will be discussed.
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Affiliation(s)
- Christina L Addison
- Center for Cancer Therapeutics, Ottawa Health Research Institute, Box 926, 501 Smyth Road, Ottawa, ON, Canada.
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40
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Hebbar M, Ernst O, Cattan S, Dominguez S, Oprea C, Mathurin P, Triboulet JP, Paris JC, Pruvot FR. Phase II Trial of Docetaxel Therapy in Patients with Advanced Hepatocellular Carcinoma. Oncology 2006; 70:154-8. [PMID: 16645329 DOI: 10.1159/000093007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2005] [Accepted: 02/25/2006] [Indexed: 01/13/2023]
Abstract
OBJECTIVES We assessed the safety and efficacy of docetaxel, a microtubule inhibitor, in patients with advanced hepatocellular carcinoma (HCC). METHODS HCC patients that were not suitable for local therapy, but who possessed measurable disease, good performance status and adequate organ function were eligible. Docetaxel was administered every 3 weeks at a dose of 100 mg/m(2) (or 75 mg/m(2) if transaminase levels were between 1.5 and 3.5 times the upper normal limit). Efficacy was assessed radiologically every three cycles of chemotherapy. RESULTS Fifteen patients were enrolled: 11 males and 4 females; their median age was 64 years (range, 42-72 years). Nine patients had underlying cirrhosis. Four patients had been surgically treated before relapse (liver resection in 3 cases and transplantation in 1), 3 had been treated with arterial chemoembolization and 1 with arterial chemotherapy (doxorubicin). A total of 57 cycles of docetaxel were delivered (median 3, range 1-6). Significant toxicity was observed: mostly grade 3-4 neutropenia and fatigue (6 and 4 patients, respectively). Treatment had to be stopped because of toxicity in 6 patients, all having underlying cirrhosis. An important partial response was obtained in 1 patient, a result that enabled liver transplantation; this patient is still alive after 34 months. Five patients had transient stable disease. CONCLUSION When used in this schedule, docetaxel does not appear to be safe and effective enough in patients with advanced HCC and cirrhosis.
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Affiliation(s)
- Mohamed Hebbar
- Unité d'Oncologie Médicale, Centre Hospitalo-Universitaire, Lille, France.
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Wu XZ, Chen D, Xie GR. Extracellular matrix remodeling in hepatocellular carcinoma: effects of soil on seed? Med Hypotheses 2006; 66:1115-20. [PMID: 16504415 DOI: 10.1016/j.mehy.2005.12.043] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2005] [Accepted: 12/23/2005] [Indexed: 12/16/2022]
Abstract
Extracellular matrix plays two-edged roles, inhibitor and promoter, in the carcinogenesis and progression of hepatocellular carcinoma. On the one hand, extracellular matrix provides the survival signals, and controls the proliferation, differentiation and metastasis of hepatocellular carcinoma. On the other hand, hepatocarcinoma cells create a permissive soil by extracellular matrix remodeling, result in high proliferation, low differentiation, apoptosis block, invasion and metastasis. These malignant phenotypes are related with the change of the capsule around hepatocarcinoma cells that composed by collagens I and IV, the cell-extracellular matrix interaction induced by laminin and its receptor-integrins, and the degradation of ECM which is regulated by proteolytic enzymes and their inhibitor. Thus, normalization of ECM may represent a novel therapeutic strategy for hepatocarcinoma cells.
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Affiliation(s)
- Xiong Zhi Wu
- Cancer Hospital of Tianjin, Tianjin Medical University, Ti-Yuan-Bei, He Xi District, China.
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Tao Y, Wei Q, Xu Z, Bai R, Li Y, Luo C, Dong Y, Gao G, Lu Y. Holistic and network analysis of meningioma pathogenesis and malignancy. Biofactors 2006; 28:203-19. [PMID: 17473381 DOI: 10.1002/biof.5520280307] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Meningiomas, which originate from arachnoid cells and constitute the largest subgroup of all intracranial tumors, are generally benign, yet have the capacity to progress into a higher histological grade of malignancy associated with an increase in biological aggressivity and/or capacity to recur. To elucidate meningioma pathogenesis and malignancy, we applied a holistic and network approach analyzing cDNA and tissue microarray results. A potential pathway leading to meningioma angiogenesis, apoptosis and proliferation was evidenced as well as a regulatory network of the biomarkers including Ki-67, AR, CD34, P53, c-MYC, etc. which might support clinical research. In this potential pathway, ITGB1 could be the most important "superoncogene" playing a vital role in apoptosis and proliferation, while FOXO3A, MDM4 and MT3 are important to the malignancy process. Some genes are first reported that could explain why radiation induces meningioma and why more female than male patients are affected. Further, we present the hypothesis that HIV-Tat protein might have a close relationship with meningioma pathogenesis and malignancy.
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Affiliation(s)
- Yingqun Tao
- Department of Neurosurgery, The General Hospital of Shenyang Military Region, Shenyang, P.R. China.
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Andjilani M, Droz JP, Benahmed M, Tabone E. Alpha6 integrin subunit mediates laminin enhancement of cisplatin-induced apoptosis in testicular tumor germ cells. Int J Cancer 2005; 117:68-81. [PMID: 15880592 DOI: 10.1002/ijc.21144] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Our study demonstrates that laminin potentiates cisplatin-induced apoptosis in NCCIT, a testicular tumor germ cell line. When cultured on laminin, NCCIT cells displayed a significantly higher susceptibility to cisplatin-induced apoptosis than on plastic or on other ECM components including fibronectin, Type IV collagen and vitronectin. This high cisplatin sensitivity observed on NCCIT cell cultured on laminin was mediated by the alpha6-integrin signaling. The knockdown of the alpha6-integrin subunit by small interfering RNAs suppressed the higher cisplatin-sensitivity supporting the existence of a crosstalk between laminin-alpha6-integrin signaling and cisplatin-induced apoptosis. Our findings indicate that in cisplatin-treated NCCIT cells, the laminin-alpha6-integrin signaling induces the activation of executioner procaspase-3 and -6 as well as apoptosis-inducing factor (AIF) transcription and expression. The ability of integrin-mediated specific stroma-tumor cell interactions to modulate the chemosensitive phenotype of a tumor cell might provide new insights to overcome cisplatin resistance of tumor cells.
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Fang H, Tong W, Perkins R, Shi L, Hong H, Cao X, Xie Q, Yim SH, Ward JM, Pitot HC, Dragan YP. Bioinformatics approaches for cross-species liver cancer analysis based on microarray gene expression profiling. BMC Bioinformatics 2005; 6 Suppl 2:S6. [PMID: 16026603 PMCID: PMC1637037 DOI: 10.1186/1471-2105-6-s2-s6] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background The completion of the sequencing of human, mouse and rat genomes and knowledge of cross-species gene homologies enables studies of differential gene expression in animal models. These types of studies have the potential to greatly enhance our understanding of diseases such as liver cancer in humans. Genes co-expressed across multiple species are most likely to have conserved functions. We have used various bioinformatics approaches to examine microarray expression profiles from liver neoplasms that arise in albumin-SV40 transgenic rats to elucidate genes, chromosome aberrations and pathways that might be associated with human liver cancer. Results In this study, we first identified 2223 differentially expressed genes by comparing gene expression profiles for two control, two adenoma and two carcinoma samples using an F-test. These genes were subsequently mapped to the rat chromosomes using a novel visualization tool, the Chromosome Plot. Using the same plot, we further mapped the significant genes to orthologous chromosomal locations in human and mouse. Many genes expressed in rat 1q that are amplified in rat liver cancer map to the human chromosomes 10, 11 and 19 and to the mouse chromosomes 7, 17 and 19, which have been implicated in studies of human and mouse liver cancer. Using Comparative Genomics Microarray Analysis (CGMA), we identified regions of potential aberrations in human. Lastly, a pathway analysis was conducted to predict altered human pathways based on statistical analysis and extrapolation from the rat data. All of the identified pathways have been known to be important in the etiology of human liver cancer, including cell cycle control, cell growth and differentiation, apoptosis, transcriptional regulation, and protein metabolism. Conclusion The study demonstrates that the hepatic gene expression profiles from the albumin-SV40 transgenic rat model revealed genes, pathways and chromosome alterations consistent with experimental and clinical research in human liver cancer. The bioinformatics tools presented in this paper are essential for cross species extrapolation and mapping of microarray data, its analysis and interpretation.
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Affiliation(s)
- H Fang
- Division of Bioinformatics, Z-Tech Corporation, 3900 NCTR Road, Jefferson, AR 72079
| | - W Tong
- Division of Systems Toxicology, National Center for Toxicological Research (NCTR), FDA, 3900 NCTR Road, Jefferson, AR 72079
| | - R Perkins
- Division of Bioinformatics, Z-Tech Corporation, 3900 NCTR Road, Jefferson, AR 72079
| | - L Shi
- Division of Systems Toxicology, National Center for Toxicological Research (NCTR), FDA, 3900 NCTR Road, Jefferson, AR 72079
| | - H Hong
- Division of Bioinformatics, Z-Tech Corporation, 3900 NCTR Road, Jefferson, AR 72079
| | - X Cao
- Division of Bioinformatics, Z-Tech Corporation, 3900 NCTR Road, Jefferson, AR 72079
| | - Q Xie
- Division of Bioinformatics, Z-Tech Corporation, 3900 NCTR Road, Jefferson, AR 72079
| | - SH Yim
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892
| | - JM Ward
- Verterinary and Tumor Pathology Section, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702
| | - HC Pitot
- McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706
| | - YP Dragan
- Division of Systems Toxicology, National Center for Toxicological Research (NCTR), FDA, 3900 NCTR Road, Jefferson, AR 72079
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Zhang Y, Fan XG, Chen R, Xiao ZQ, Feng XP, Tian XF, Chen ZH. Comparative proteome analysis of untreated and Helicobacter pylori-treated HepG2. World J Gastroenterol 2005; 11:3485-9. [PMID: 15948260 PMCID: PMC4316009 DOI: 10.3748/wjg.v11.i22.3485] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the pathological effect of Helicobacter pylori (H pylori) on human hepatic cells, proteomic methods were used to find and to identify proteins that were overexpressed in HepG2 cells treated by H pylori.
METHODS: H pylori was co-cultured with HepG2 for 6 h. Two-dimensional gel electrophoresis was used to gain the protein expression pattern of untreated and H pylori-treated HepG2. After staining and image analysis, spots of interest were isolated and subjected to mass spectrometry.
RESULTS: Seven proteins, which were up-regulated in H pylori-treated HepG2 cells, were identified. These proteins included integrin beta-1, protein kinase C alpha, LIM/homeobox protein Lhx1, eIF-2-beta, MAP kinase kinase 3, PINCH protein and Ras-related protein Rab-37, which involved in transcription regulation, signal transduction, metabolism and so on.
CONCLUSION: H pylori may exert the pathological effect on HepG2 cells by up-regulating the expression of some proteins.
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Affiliation(s)
- Yan Zhang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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Schaefer KL, Wada K, Takahashi H, Matsuhashi N, Ohnishi S, Wolfe MM, Turner JR, Nakajima A, Borkan SC, Saubermann LJ. Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells. Cancer Res 2005; 65:2251-9. [PMID: 15781638 DOI: 10.1158/0008-5472.can-04-3037] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Activation of the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits growth and survival of hepatocellular carcinoma (HCC) cell lines. To further investigate the function of PPARgamma in HCC, PPARgamma expression patterns in primary tumors were examined, and the responses of two HCC cell lines to PPARgamma activation and inhibition were compared. PPARgamma expression was increased in HCC and benign-appearing peritumoral hepatocytes compared with remote benign hepatocytes. Both compound PPARgamma inhibitors and PPARgamma small interfering RNAs prevented HCC cell lines from adhering to the extracellular matrix. Loss of adhesion was followed by caspase-dependent apoptosis (anoikis). PPARgamma inhibitors had no effect on initial beta1 integrin-mediated adhesion, or on total focal adhesion kinase levels but did reduce focal adhesion kinase phosphorylation. The PPARgamma inhibitor T0070907 was significantly more efficient at causing cancer cell death than the activators troglitazone and rosiglitazone. T0070907 caused cell death by reducing adhesion and inducing anoikis, whereas the activators had no direct effect on adhesion and caused cell death at much higher concentrations. In conclusion, PPARgamma overexpression is present in HCC. Inhibition of PPARgamma function causes HCC cell death by preventing adhesion and inducing anoikis-mediated apoptosis. PPARgamma inhibitors represent a potential novel treatment approach to HCC.
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He R, Leeson A, Ballantine M, Andonov A, Baker L, Dobie F, Li Y, Bastien N, Feldmann H, Strocher U, Theriault S, Cutts T, Cao J, Booth TF, Plummer FA, Tyler S, Li X. Characterization of protein-protein interactions between the nucleocapsid protein and membrane protein of the SARS coronavirus. Virus Res 2005; 105:121-5. [PMID: 15351485 PMCID: PMC7127797 DOI: 10.1016/j.virusres.2004.05.002] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2004] [Revised: 05/07/2004] [Accepted: 05/10/2004] [Indexed: 02/04/2023]
Abstract
The human coronavirus, associated with severe acute respiratory syndrome (SARS-CoV), was identified and molecularly characterized in 2003. Sequence analysis of the virus indicates that there is only 20% amino acid (aa) identity with known coronaviruses. Previous studies indicate that protein-protein interactions amongst various coronavirus proteins are critical for viral assembly. Yet, little sequence homology between the newly identified SARS-CoV and those previously studied coronaviruses suggests that determination of protein-protein interaction and identification of amino acid sequences, responsible for such interaction in SARS-CoV, are necessary for the elucidation of the molecular mechanism of SARS-CoV replication and rationalization of anti-SARS therapeutic intervention. In this study, we employed mammalian two-hybrid system to investigate possible interactions between SARS-CoV nucleocapsid (N) and the membrane (M) proteins. We found that interaction of the N and M proteins takes place in vivo and identified that a stretch of amino acids (168-208) in the N protein may be critical for such protein-protein interactions. Importantly, the same region has been found to be required for multimerization of the N protein (He et al., 2004) suggesting this region may be crucial in maintaining correct conformation of the N protein for self-interaction and interaction with the M protein.
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Affiliation(s)
- Runtao He
- National Microbiology Laboratory, Health Canada, 1015 Arlington St., Winnipeg, Man., Canada R3E 3R2.
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Affiliation(s)
- David Semela
- Institute of Clinical Pharmacology, University of Bern, 35 Murtenstrasse, Bern CH-3010, Switzerland
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Zhang H, Ozaki I, Mizuta T, Yoshimura T, Matsuhashi S, Eguchi Y, Yasutake T, Hisatomi A, Sakai T, Yamamoto K. Transforming growth factor-beta 1-induced apoptosis is blocked by beta 1-integrin-mediated mitogen-activated protein kinase activation in human hepatoma cells. Cancer Sci 2004; 95:878-86. [PMID: 15546505 PMCID: PMC11158769 DOI: 10.1111/j.1349-7006.2004.tb02197.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2004] [Revised: 08/05/2004] [Accepted: 09/02/2004] [Indexed: 12/22/2022] Open
Abstract
Growth factors and extracellular matrices cooperatively regulate cellular behavior. However, the interactions between transforming growth factor-beta 1 (TGF-beta 1) and integrins in hepatic cells are not fully understood. We investigated the effects of beta 1-integrin on TGF-beta 1-regulated growth of hepatoma cells. Human hepatoma cell lines HepG2, Huh7, and Hep3B were stably transfected with beta 1-integrin, and the parental, and mock- and beta 1-integrin-transfected hepatoma cells were treated with TGF-beta 1. Modulation of apoptosis and pathways involved in the process were investigated. TGF-beta 1 suppressed the growth of hepatoma cells, and apoptosis was observed in Hep3B and Huh7. Hepatoma cells transfected with beta 1-integrin were protected from TGF-beta 1-induced apoptosis. Mitogen-activated protein (MAP) kinase inhibitors, PD98059, SB203580, and SP600125, abolished this protective effect of beta 1-integrin, but herbimycin A and wortmannin were ineffective. Hepatoma cells overexpressing beta 1-integrin showed increased activities of MAP kinases, and TGF-beta 1 induced sustained activation of MAP kinases in these cells, but only transient activation in mock-transfected cells. These data suggest that MAP kinases activated by beta 1-integrin provide a strong anti-apoptotic signal during TGF-beta 1-induced apoptosis in human hepatoma cells. Therefore beta 1-integrin-mediated signals may contribute to the development and progression of hepatocellular carcinoma.
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Affiliation(s)
- Hao Zhang
- Division of Hepatology and Metabolism, Department of Internal Medicine, Saga Medical School, Saga University, Saga 849-8501
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Cai Q, Lanting L, Natarajan R. Interaction of monocytes with vascular smooth muscle cells regulates monocyte survival and differentiation through distinct pathways. Arterioscler Thromb Vasc Biol 2004; 24:2263-70. [PMID: 15458980 DOI: 10.1161/01.atv.0000146552.16943.5e] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Vascular smooth muscle cells (VSMCs) may regulate monocyte functions within atherosclerotic lesions. We investigated the impact of VSMC/monocyte interactions on monocyte apoptosis and scavenger receptor CD36 expression, key events related to monocyte survival and differentiation. METHODS AND RESULTS Serum deprivation significantly increased THP-1 and human peripheral blood monocyte apoptosis. However, this was significantly reversed by physical binding to human VSMCs (HVSMCs). On binding to HVSMCs, antiapoptotic kinase Akt and its downstream targets were phosphorylated, and Bcl-2 expression was enhanced. Binding-mediated suppression of apoptosis and Akt phosphorylation were attenuated by a phosphoinositide 3-kinase inhibitor and also by an antibody to vascular cell adhesion molecule-1. CD36 expression was also significantly increased in THP-1 cells and in human peripheral blood monocytes after binding to HVSMCs, and this was mediated by both direct contact and soluble factors. Extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase phosphorylation was increased in THP-1 cells after HVSMC coculture. Furthermore, an ERK1/2 inhibitor blocked monocyte CD36 upregulation. Contact-dependent CD36 induction and ERK1/2 phosphorylation in monocytes were inhibited by blocking vascular cell adhesion molecule-1 on HVSMC, whereas soluble factor-induced CD36 expression was attenuated by a monocyte chemoattractant protein-1 neutralizing antibody. CONCLUSIONS These data provide evidence of novel VSMC-dependent local regulation mechanisms for monocyte survival and differentiation in atherosclerosis.
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Affiliation(s)
- Qiangjun Cai
- Gonda Goldschmied Diabetes Center, Beckman Research Institute of City of Hope, Duarte, CalifA 91010, USA
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