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1
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Li Y, Zhu J, Zhai F, Kong L, Li H, Jin X. Advances in the understanding of nuclear pore complexes in human diseases. J Cancer Res Clin Oncol 2024; 150:374. [PMID: 39080077 PMCID: PMC11289042 DOI: 10.1007/s00432-024-05881-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/03/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Nuclear pore complexes (NPCs) are sophisticated and dynamic protein structures that straddle the nuclear envelope and act as gatekeepers for transporting molecules between the nucleus and the cytoplasm. NPCs comprise up to 30 different proteins known as nucleoporins (NUPs). However, a growing body of research has suggested that NPCs play important roles in gene regulation, viral infections, cancer, mitosis, genetic diseases, kidney diseases, immune system diseases, and degenerative neurological and muscular pathologies. PURPOSE In this review, we introduce the structure and function of NPCs. Then We described the physiological and pathological effects of each component of NPCs which provide a direction for future clinical applications. METHODS The literatures from PubMed have been reviewed for this article. CONCLUSION This review summarizes current studies on the implications of NPCs in human physiology and pathology, highlighting the mechanistic underpinnings of NPC-associated diseases.
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Affiliation(s)
- Yuxuan Li
- The Affiliated Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Nngbo University, Ningbo, 315211, Zhejiang, China
| | - Jie Zhu
- The Affiliated Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Fengguang Zhai
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Nngbo University, Ningbo, 315211, Zhejiang, China
| | - Lili Kong
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Nngbo University, Ningbo, 315211, Zhejiang, China
| | - Hong Li
- The Affiliated Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China.
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Nngbo University, Ningbo, 315211, Zhejiang, China.
| | - Xiaofeng Jin
- The Affiliated Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China.
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Nngbo University, Ningbo, 315211, Zhejiang, China.
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2
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Tarvestad-Laise KE, Ceresa BP. Modulating Growth Factor Receptor Signaling to Promote Corneal Epithelial Homeostasis. Cells 2023; 12:2730. [PMID: 38067157 PMCID: PMC10706396 DOI: 10.3390/cells12232730] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/20/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
The corneal epithelium is the first anatomical barrier between the environment and the cornea; it is critical for proper light refraction onto the retina and prevents pathogens (e.g., bacteria, viruses) from entering the immune-privileged eye. Trauma to the highly innervated corneal epithelium is extremely painful and if not resolved quickly or properly, can lead to infection and ultimately blindness. The healthy eye produces its own growth factors and is continuously bathed in tear fluid that contains these proteins and other nutrients to maintain the rapid turnover and homeostasis of the ocular surface. In this article, we review the roles of growth factors in corneal epithelial homeostasis and regeneration and some of the limitations to their use therapeutically.
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Affiliation(s)
- Kate E. Tarvestad-Laise
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Brian P. Ceresa
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
- Department of Ophthalmology and Vision Sciences, University of Louisville, Louisville, KY 40202, USA
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3
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Crosas-Molist E, Samain R, Kohlhammer L, Orgaz J, George S, Maiques O, Barcelo J, Sanz-Moreno V. RhoGTPase Signalling in Cancer Progression and Dissemination. Physiol Rev 2021; 102:455-510. [PMID: 34541899 DOI: 10.1152/physrev.00045.2020] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Rho GTPases are a family of small G proteins that regulate a wide array of cellular processes related to their key roles controlling the cytoskeleton. On the other hand, cancer is a multi-step disease caused by the accumulation of genetic mutations and epigenetic alterations, from the initial stages of cancer development when cells in normal tissues undergo transformation, to the acquisition of invasive and metastatic traits, responsible for a large number of cancer related deaths. In this review, we discuss the role of Rho GTPase signalling in cancer in every step of disease progression. Rho GTPases contribute to tumour initiation and progression, by regulating proliferation and apoptosis, but also metabolism, senescence and cell stemness. Rho GTPases play a major role in cell migration, and in the metastatic process. They are also involved in interactions with the tumour microenvironment and regulate inflammation, contributing to cancer progression. After years of intensive research, we highlight the importance of relevant models in the Rho GTPase field, and we reflect on the therapeutic opportunities arising for cancer patients.
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Affiliation(s)
- Eva Crosas-Molist
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Remi Samain
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Leonie Kohlhammer
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Jose Orgaz
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, 28029, Madrid, Spain
| | - Samantha George
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Oscar Maiques
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Jaume Barcelo
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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4
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Morgan EL, Scarth JA, Patterson MR, Wasson CW, Hemingway GC, Barba-Moreno D, Macdonald A. E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer. Cell Death Differ 2021; 28:1669-1687. [PMID: 33303976 PMCID: PMC8166842 DOI: 10.1038/s41418-020-00693-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Human papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.
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Affiliation(s)
- Ethan L. Morgan
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.94365.3d0000 0001 2297 5165Present Address: Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, National Institute of Health, Bethesda, MD USA
| | - James A. Scarth
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Molly R. Patterson
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Christopher W. Wasson
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Present Address: Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, St-James University Teaching Hospital, Leeds, West Yorkshire UK
| | - Georgia C. Hemingway
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Diego Barba-Moreno
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
| | - Andrew Macdonald
- grid.9909.90000 0004 1936 8403School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT UK ,grid.9909.90000 0004 1936 8403Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire LS2 9JT UK
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5
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Godwin I, Anto NP, Bava SV, Babu MS, Jinesh GG. Targeting K-Ras and apoptosis-driven cellular transformation in cancer. Cell Death Discov 2021; 7:80. [PMID: 33854056 PMCID: PMC8047025 DOI: 10.1038/s41420-021-00457-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/23/2021] [Accepted: 03/21/2021] [Indexed: 02/07/2023] Open
Abstract
Cellular transformation is a major event that helps cells to evade apoptosis, genomic instability checkpoints, and immune surveillance to initiate tumorigenesis and to promote progression by cancer stem cell expansion. However, the key molecular players that govern cellular transformation and ways to target cellular transformation for therapy are poorly understood to date. Here we draw key evidences from the literature on K-Ras-driven cellular transformation in the context of apoptosis to shed light on the key players that are required for cellular transformation and explain how aiming p53 could be useful to target cellular transformation. The defects in key apoptosis regulators such as p53, Bax, and Bak lead to apoptosis evasion, cellular transformation, and genomic instability to further lead to stemness, tumorigenesis, and metastasis via c-Myc-dependent transcription. Therefore enabling key apoptotic checkpoints in combination with K-Ras inhibitors will be a promising therapeutic target in cancer therapy.
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Affiliation(s)
- Isha Godwin
- Saveetha Medical College, Thandalam, Chennai, Tamil Nadu, 602105, India.
| | - Nikhil Ponnoor Anto
- Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beersheba, Israel
| | - Smitha V Bava
- Department of Biotechnology, University of Calicut, Malappuram, Kerala, 673635, India
| | - Mani Shankar Babu
- Department of Botany, University College, Thiruvananthapuram, Kerala, 695 034, India
| | - Goodwin G Jinesh
- Departments of Molecular Oncology, and Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
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Lopusna K, Nowialis P, Opavska J, Abraham A, Riva A, Opavsky R. Dnmt3b catalytic activity is critical for its tumour suppressor function in lymphomagenesis and is associated with c-Met oncogenic signalling. EBioMedicine 2021; 63:103191. [PMID: 33418509 PMCID: PMC7804970 DOI: 10.1016/j.ebiom.2020.103191] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 12/10/2020] [Accepted: 12/14/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND DNA methylation regulates gene transcription in many physiological processes in mammals including development and haematopoiesis. It is catalysed by several DNA methyltransferases, including Dnmt3b that mediates both methylation-dependant and independent gene repression. Dnmt3b is critical for mouse embryogenesis and functions as a tumour suppressor in haematologic malignancies in mice. However, the extent to which Dnmt3b's catalytic activity (CA) is involved in development and cancer is unclear. METHODS We used a mouse model expressing catalytically inactive Dnmt3b (Dnmt3bCI) to study a role of Dnmt3b's CA in development and cancer. We utilized global approaches including Whole-genome Bisulfite sequencing and RNA-seq to analyse DNA methylation and gene expression to identify putative targets of Dnmt3b's CA. To analyse postnatal development and haematopoiesis, we used tissue staining, histological and FACS analysis. To determine potential involvement of selected genes in lymphomagenesis, we used overexpression and knock down approaches followed by in vitro growth assays. FINDINGS We show that mice expressing Dnmt3bCI only, survive postnatal development and develop ICF (the immunodeficiency-centromeric instability-facial anomalies) -like syndrome. The lack of Dnmt3b's CA promoted fibroblasts transformation in vitro, accelerated MLL-AF9 driven Acute Myeloid Leukaemia and MYC-induced T-cell lymphomagenesis in vivo. The elimination of Dnmt3b's CA resulted in decreased methylation of c-Met promoter and its upregulation, activated oncogenic Met signalling, Stat3 phosphorylation and up-regulation of Lin28b promoting lymphomagenesis. INTERPRETATION Our data demonstrates that Dnmt3b's CA is largely dispensable for mouse development but critical to prevent tumourigenesis by controlling events involved in cellular transformation. FUNDING This study was supported by Department of Anatomy and Cell Biology and Cancer Centre at the University of Florida start-up funds, NIH/NCI grant 1R01CA188561-01A1 (R.O.).
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Affiliation(s)
- Katarina Lopusna
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, 2033 Mowry Rd, CGRC 258, Gainesville, FL 32610, United States
| | - Pawel Nowialis
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, 2033 Mowry Rd, CGRC 258, Gainesville, FL 32610, United States
| | - Jana Opavska
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, 2033 Mowry Rd, CGRC 258, Gainesville, FL 32610, United States
| | - Ajay Abraham
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, 2033 Mowry Rd, CGRC 258, Gainesville, FL 32610, United States
| | - Alberto Riva
- ICBR Bioinformatics, Cancer and Genetics Research Complex, University of Florida, P.O. Box 103622. Gainesville, FL 32610, United States
| | - Rene Opavsky
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, 2033 Mowry Rd, CGRC 258, Gainesville, FL 32610, United States.
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7
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Wang H, Rao B, Lou J, Li J, Liu Z, Li A, Cui G, Ren Z, Yu Z. The Function of the HGF/c-Met Axis in Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 8:55. [PMID: 32117981 PMCID: PMC7018668 DOI: 10.3389/fcell.2020.00055] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/22/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, leading to a large global cancer burden. Hepatocyte growth factor (HGF) and its high-affinity receptor, mesenchymal epithelial transition factor (c-Met), are closely related to the onset, progression, and metastasis of multiple tumors. The HGF/c-Met axis is involved in cell proliferation, movement, differentiation, invasion, angiogenesis, and apoptosis by activating multiple downstream signaling pathways. In this review, we focus on the function of the HGF/c-Met axis in HCC. The HGF/c-Met axis promotes the onset, proliferation, invasion, and metastasis of HCC. Moreover, it can serve as a biomarker for diagnosis and prognosis, as well as a therapeutic target for HCC. In addition, it is closely related to drug resistance during HCC treatment.
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Affiliation(s)
- Haiyu Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Benchen Rao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiamin Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhao Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenguo Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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8
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Hervieu A, Kermorgant S. The Role of PI3K in Met Driven Cancer: A Recap. Front Mol Biosci 2018; 5:86. [PMID: 30406111 PMCID: PMC6207648 DOI: 10.3389/fmolb.2018.00086] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/10/2018] [Indexed: 12/27/2022] Open
Abstract
The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. However RTK inhibitors can lead to drug resistance, explaining the necessity to develop therapies that target downstream signaling. Phosphatidylinositide 3-kinase (PI3K) is one of the most deregulated pathways in cancer and implicated in various types of cancer. PI3K signaling is also a major signaling pathway downstream of RTK, including Met. PI3K major effectors include Akt and "mechanistic Target of Rapamycin" (mTOR), which each play key roles in numerous and various cell functions. Advancements made due to the development of molecular and pharmaceutical tools now allow us to delve into the roles of each independently. In this review, we summarize the current understanding we possess of the activation and role of PI3K/Akt/mTOR, downstream of Met, in cancer.
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Affiliation(s)
- Alexia Hervieu
- Signal Transduction and Molecular Pharmacology Team, Cancer Therapeutics Division, Institute of Cancer Research, Sutton, United Kingdom
- Spatial Signalling Team, Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stéphanie Kermorgant
- Spatial Signalling Team, Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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9
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Li S, Yang L, Wang J, Liang F, Chang B, Gu H, Wang H, Yang G, Chen Y. Analysis of the chemotherapeutic effects of a propadiene compound on malignant ovarian cancer cells. Oncotarget 2018; 7:57145-57159. [PMID: 27494891 PMCID: PMC5302979 DOI: 10.18632/oncotarget.11012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 07/19/2016] [Indexed: 12/31/2022] Open
Abstract
Epithelial ovarian cancer is most lethal in female reproductive carcinomas owing to the high chemoresistance and metastasis, so more efficient therapeutic agents are terribly needed. A propadiene compound: 1-phenylpropadienyl phosphine oxide (PHPO), was employed to test the chemotherapeutic efficacy against ovarian cancer cell lines. MTT assay showed that PHPO displayed a much lower IC50 than cisplatin and paclitaxel, while combination treatment of cells with PHPO + cisplatin induced more apoptosis than with PHPO + paclitaxel or with cisplatin + paclitaxel (p < 0.05). Animal assays demonstrated that subcutaneous tumor growth was highly inhibited by PHPO + cisplatin, compared with that inhibited by PHPO or by cisplatin treatment alone, indicating PHPO and cisplatin may have synergistic effects against ovarian cancer growth. We also found that PHPO induced few side effects on animals, compared with cisplatin. Mechanistic studies suggested that treatment of cells with PHPO or with PHPO + cisplatin differentially inhibited the PI3K/Akt, MAPK and ATM/Chk2 pathways, which consequently suppressed the anti-apoptotic factors Bcl-xL, Bcl-2 and XIAP, but activated the pro-apoptotic factors Bad, Bax, p53, caspase 9, caspase 8, caspase 7 and PARP. Taken together, PHPO may induce cell apoptosis through multiple signal pathways, especially when used along with cisplatin. Therefore, PHPO may be explored as a prospective agent to effectively treat ovarian cancer.
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Affiliation(s)
- Shuqing Li
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Lina Yang
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Jingshu Wang
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Fan Liang
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Bin Chang
- Department of Pathology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Huafen Gu
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Honglin Wang
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Gong Yang
- Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Central laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Yaping Chen
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China
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10
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Liu H, Wang X, Han R, Zuo K, Yuan X, Li Y, Zhou J, Yan L, Chu Y. Isolation and molecular cloning of hepatocyte growth factor from guinea pig (gHGF), and expression of truncated variant of gHGF with improved anti-fibrotic activity in Escherichia coli. Int J Biol Macromol 2018; 106:908-916. [DOI: 10.1016/j.ijbiomac.2017.08.087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 08/12/2017] [Accepted: 08/14/2017] [Indexed: 02/07/2023]
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11
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Wang J, Tai G. Role of C-Jun N-terminal Kinase in Hepatocellular Carcinoma Development. Target Oncol 2017; 11:723-738. [PMID: 27392951 DOI: 10.1007/s11523-016-0446-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is among the most frequently occurring cancers and the leading causes of cancer mortality worldwide. Identification of the signaling pathways regulating liver carcinogenesis is critical for developing novel chemoprevention and targeted therapies. C-Jun N-terminal kinase (JNK) is a member of a larger group of serine/threonine (Ser/Thr) protein kinases known as the mitogen-activated protein kinase (MAPK) family. JNK is an important signaling component that converts external stimuli into a wide range of cellular responses, including cell proliferation, differentiation, survival, migration, invasion, and apoptosis, as well as the development of inflammation, fibrosis, cancer growth, and metabolic diseases. Because of the essential roles of JNK in these cellular functions, deregulated JNK is often found to contribute to the development of HCC. Recently, the functions and molecular mechanisms of JNK in HCC development have been addressed using mouse models and human HCC cell lines. Furthermore, recent studies demonstrate that the activation of JNK by oncogenes can promote the development of cancers by regulating the transforming growth factor (TGF)-β/Smad pathway, which makes the oncogenes/JNK/Smad signaling pathway an attractive target for cancer therapy. Additionally, JNK-targeted therapy has a broad potential for clinical applications. In summary, we are convinced that promising new avenues for the treatment of HCC by targeting JNK are on the horizon, which will undoubtedly lead to better, more effective, and faster therapies in the years to come.
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Affiliation(s)
- Juan Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Jilin, Changchun, 130021, China
| | - Guixiang Tai
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Jilin, Changchun, 130021, China.
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12
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Novel tumor-suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemia. Exp Hematol 2017; 53:16-25. [PMID: 28479419 DOI: 10.1016/j.exphem.2017.04.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 04/21/2017] [Accepted: 04/22/2017] [Indexed: 02/07/2023]
Abstract
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients. Despite advances in the treatment of this disease, many children with T-cell ALL (T-ALL) die from disease relapse due to low responses to standard chemotherapy and the lack of a targeted therapy that selectively eradicates the chemoresistant leukemia-initiating cells (LICs) responsible for disease recurrence. We reported recently that the reprogramming factor Krüppel-like factor 4 (KLF4) has a tumor-suppressive function in children with T-ALL. KLF4 silencing by promoter deoxyribonucleic acid (DNA) methylation in patients with T-ALL leads to aberrant activation of the mitogen-activated protein kinase kinase MAP2K7 and the downstream c-Jun NH2-terminal kinase (JNK) pathway that controls the expansion of leukemia cells via c-Jun and activating transcription factor 2. This pathway can be inhibited with small molecules and therefore has the potential to eliminate LICs and eradicate disease in combination with standard therapy for patients with refractory and relapsed disease. The present review summarizes the role of the KLF4-MAP2K7 pathway in T-ALL pathogenesis and the function of JNK and MAP2K7 in carcinogenesis and therapy.
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Wang J, Ni WH, Hu KB, Zhai XY, Xie F, Jie J, Zhang NN, Jiang LN, Yuan HY, Tai GX. Targeting MUC1 and JNK by RNA interference and inhibitor inhibit the development of hepatocellular carcinoma. Cancer Sci 2017; 108:504-511. [PMID: 28012230 PMCID: PMC5378288 DOI: 10.1111/cas.13144] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 12/14/2016] [Accepted: 12/18/2016] [Indexed: 02/06/2023] Open
Abstract
Mucin 1 (MUC1), as an oncogene, is overexpressed in hepatocellular carcinoma (HCC) cells and promotes the progression and tumorigenesis of HCC through JNK/TGF-β signaling pathway. In the present study, RNA interference (RNAi) and JNK inhibitor SP600125, which target MUC1 and/or JNK, were used to treat HCC cells in vitro, and the results showed that both silencing the expression of MUC1 and blocking the activity of JNK inhibited the proliferation of HCC cells. In addition, MUC1-stable-knockdown and SP600125 significantly inhibited the growth of tumors in the subcutaneous transplant tumor models that established in BALB/c nude mice rather than MUC1 or JNK siRNAs transiently transfection. Furthermore, the results from immunohistochemical staining assays showed that the inhibitory effects of MUC1 gene silencing and SP600125 on the proliferation of HCC cells in vivo were through the JNK/TGF-β signaling pathway. These results indicate that MUC1 and JNK are attractive targets for HCC therapy and may provide new therapeutic strategies for the treatment of HCC.
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Affiliation(s)
- Juan Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Wei-Hua Ni
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Ke-Bang Hu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Xiao-Yu Zhai
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Fei Xie
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Jing Jie
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Nan-Nan Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Li-Na Jiang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Hong-Yan Yuan
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Gui-Xiang Tai
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
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14
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Park T, Koptyra M, Curran T. Fibroblast Growth Requires CT10 Regulator of Kinase (Crk) and Crk-like (CrkL). J Biol Chem 2016; 291:26273-26290. [PMID: 27807028 DOI: 10.1074/jbc.m116.764613] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Indexed: 12/12/2022] Open
Abstract
CT10 regulator of kinase (Crk) and Crk-like (CrkL) are the cellular counterparts of the viral oncogene v-Crk Elevated levels of Crk and CrkL have been observed in many human cancers; inhibition of Crk and CrkL expression reduced the tumor-forming potential of cancer cell lines. Despite a close relationship between the Crk family proteins and tumorigenesis, how Crk and CrkL contribute to cell growth is unclear. We ablated endogenous Crk and CrkL from cultured fibroblasts carrying floxed alleles of Crk and CrkL by transfection with synthetic Cre mRNA (synCre). Loss of Crk and CrkL induced by synCre transfection blocked cell proliferation and caused shrinkage of the cytoplasm and the nucleus, formation of adherens junctions, and reduced cell motility. Ablation of Crk or CrkL alone conferred a much more modest reduction in cell proliferation. Reintroduction of CrkI, CrkII, or CrkL individually rescued cell proliferation in the absence of the endogenous Crk and CrkL, suggesting that Crk and CrkL play overlapping functions in regulating fibroblast growth. Serum and basic FGF induced phosphorylation of Akt, MAP kinases, and S6 kinase and Fos expression in the absence of Crk and CrkL, suggesting that cells lacking Crk and CrkL are capable of initiating major signal transduction pathways in response to extracellular stimuli. Furthermore, cell cycle and cell death analyses demonstrated that fibroblasts lacking Crk and CrkL become arrested at the G1-S transition and undergo a modest apoptosis. Taken together, our results suggest that Crk and CrkL play essential overlapping roles in fibroblast growth.
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Affiliation(s)
- Taeju Park
- From the Children's Research Institute, Children's Mercy Kansas City, Kansas City, Missouri 64108
| | - Mateusz Koptyra
- From the Children's Research Institute, Children's Mercy Kansas City, Kansas City, Missouri 64108
| | - Tom Curran
- From the Children's Research Institute, Children's Mercy Kansas City, Kansas City, Missouri 64108
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15
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Suzuki S, Okada M, Shibuya K, Seino M, Sato A, Takeda H, Seino S, Yoshioka T, Kitanaka C. JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells. Oncotarget 2016; 6:458-70. [PMID: 25473894 PMCID: PMC4381607 DOI: 10.18632/oncotarget.2693] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 11/03/2014] [Indexed: 12/11/2022] Open
Abstract
Chemoresistance associated with cancer stem cells (CSCs), which is now being held responsible for the pervasive therapy resistance of pancreatic cancer, poses a major challenge to the successful management of this devastating malignancy. However, the molecular mechanism underlying the marked chemoresistance of pancreatic CSCs remains largely unknown. Here we show that JNK, which is upregulated in pancreatic CSCs and contributes to their maintenance, is critically involved in the resistance of pancreatic CSCs to 5-fluorouracil (5-FU) and gemcitabine (GEM). We found that JNK inhibition effectively sensitizes otherwise chemoresistant pancreatic CSCs to 5-FU and GEM. Significantly, JNK inhibition promoted 5-FU- and GEM-induced increase in intracellular reactive oxygen species (ROS), and scavenging intracellular ROS by use of N-acetylcysteine impaired JNK inhibition-mediated promotion of the cytotoxicity of 5-FU and GEM. Our findings thus suggest that JNK may contribute to the chemoresistance of pancreatic CSCs through prevention of chemotherapeutic agents-induced increase in intracellular ROS. Our findings also suggest that JNK inhibition combined with 5-FU- and/or GEM-based regimens may be a rational therapeutic approach to effectively eliminate pancreatic CSCs.
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Affiliation(s)
- Shuhei Suzuki
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Regional Cancer Network, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Masashi Okada
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Keita Shibuya
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan. Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo 102-8471, Japan
| | - Manabu Seino
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Atsushi Sato
- Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Hiroyuki Takeda
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Shizuka Seino
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan. Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo 102-8471, Japan. Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Takashi Yoshioka
- Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
| | - Chifumi Kitanaka
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan. Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo 102-8471, Japan. Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata 990-9585, Japan
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Pérez-Ramírez C, Cañadas-Garre M, Jiménez-Varo E, Faus-Dáder MJ, Calleja-Hernández MÁ. MET: a new promising biomarker in non-small-cell lung carcinoma. Pharmacogenomics 2015; 16:631-47. [PMID: 25893986 DOI: 10.2217/pgs.15.11] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) leads cancer-related deaths worldwide. Mutations in the kinase domain of the EGFR gene provide sensitivity to tyrosine kinase inhibitors (TKI) drugs. TKI show initial response rates over 75% in mutant EGFR-NSCLC patients, although most of these patients acquire resistance to EGFR inhibitors after therapy. EGFR-TKI resistance mechanisms include amplification in MET and its ligand, and also MET mutations. MET signaling dysregulation has been involved in tumor cell growth, survival, migration and invasion, angiogenesis and activation of several pathways, therefore representing an attractive target for anticancer drug development. In this review, we will discuss MET-related mechanisms of EGFR-TKI resistance in NSCLC, as well as the main drugs targeted to inhibit MET pathway.
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Affiliation(s)
- Cristina Pérez-Ramírez
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda Fuerzas Armadas, 2, 18014 Granada, Spain
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Santhana Kumar K, Tripolitsioti D, Ma M, Grählert J, Egli KB, Fiaschetti G, Shalaby T, Grotzer MA, Baumgartner M. The Ser/Thr kinase MAP4K4 drives c-Met-induced motility and invasiveness in a cell-based model of SHH medulloblastoma. SPRINGERPLUS 2015; 4:19. [PMID: 25625039 PMCID: PMC4302160 DOI: 10.1186/s40064-015-0784-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 01/02/2015] [Indexed: 01/20/2023]
Abstract
Medulloblastoma (MB) comprises four molecularly and genetically distinct subgroups of embryonal brain tumors that develop in the cerebellum. MB mostly affects infants and children and is difficult to treat because of frequent dissemination of tumor cells within the leptomeningeal space. A potential promoter of cell dissemination is the c-Met proto-oncogene receptor tyrosine kinase, which is aberrantly expressed in many human tumors including MB. Database analysis showed that c-Met is highly expressed in the sonic hedgehog (SHH) subgroup and in a small subset of Group 3 and Group 4 MB tumors. Using a cell-based three-dimensional cell motility assay combined with live-cell imaging, we investigated whether the c-Met ligand HGF could drive dissemination of MB cells expressing high levels of c-Met, and determined downstream effector mechanisms of this process. We detected variable c-Met expression in different established human MB cell lines, and we found that in lines expressing high c-Met levels, HGF promoted cell dissemination and invasiveness. Specifically, HGF-induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK-dependent manner. Additionally, we identified the Ser/Thr kinase MAP4K4 as a novel driver of c-Met-induced invasive cell dissemination. This increased invasive motility was due to MAP4K4 control of F-actin dynamics in structures required for migration and invasion. Thus, MAP4K4 couples growth factor signaling to actin cytoskeleton regulation in tumor cells, suggesting that MAP4K4 could present a promising novel target to be evaluated for treating growth factor-induced dissemination of MB tumors of different subgroups and of other human cancers.
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Affiliation(s)
- Karthiga Santhana Kumar
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Dimitra Tripolitsioti
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Min Ma
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Jasmin Grählert
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.,Current address: Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Katja B Egli
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Giulio Fiaschetti
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Tarek Shalaby
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Michael A Grotzer
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Martin Baumgartner
- Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.,University Children's Hospital Zürich, Department of Oncology, Children's Research Center, Neuro-Oncology group, August-Forel Strasse 1, CH-8008 Zürich, Switzerland
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18
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Ashizawa AT, Cortes J. Liposomal delivery of nucleic acid-based anticancer therapeutics: BP-100-1.01. Expert Opin Drug Deliv 2014; 12:1107-20. [PMID: 25539721 DOI: 10.1517/17425247.2015.996545] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Antisense oligonucleotides, siRNA, anti-microRNA are designed to selectively bind to target mRNAs, and silence disease-causing or -associated proteins. The clinical development of nucleic acid drugs has been limited by their poor bioavailability. AREAS COVERED This review article examines the strategies that have been utilized to improve the bioavailability of nucleic acids. The chemical modifications made to nucleic acids that have improved their resistance against nuclease degradation are briefly discussed. The design of cationic and neutral lipid nanoparticles that enable the systemic delivery of nucleic acids in vivo is reviewed, and the proof-of-concept evidence that intravenous administration of nucleic acids incorporated into lipid nanoparticles leads to decreased expression of target genes in humans. Preclinical results of the neutral BP-100-1.01 nanoparticle are highlighted. EXPERT OPINION To further improve the clinical potential of nucleic acid cancer drugs, we predict research on the next generation of lipid nanoparticles will focus on: i) enhancing nucleic acid delivery to poorly vascularized tumors, as well as tumors behind the blood-brain barrier; and ii) improving the accessibility of nucleic acids to the cytoplasm by enhancing endosomal escape of nucleic acids and/or reducing exocytosis of nucleic acids to the external milieu.
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Affiliation(s)
- Ana Tari Ashizawa
- BioPath Holdings, Inc. , 4710 Bellaire Blvd Suite 210, Houston, TX 77401 , USA +1 713 385 4392 ;
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19
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Cell Lines Expressing Recombinant Transmembrane Domain–Activated Receptor Kinases as Tools for Drug Discovery. ACTA ACUST UNITED AC 2014; 19:1350-61. [DOI: 10.1177/1087057114552414] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Many receptor tyrosine kinases (RTKs) represent bona fide drug targets in oncology. Effective compounds are available, but treatment invariably leads to resistance, often due to RTK mutations. The discovery of second-generation inhibitors requires cellular models of resistant RTKs. An approach using artificial transmembrane domains (TMDs) to activate RTKs was explored for the rapid generation of simple, ligand-independent cellular RTK assays, including resistance mutants. The RTKs epidermal growth factor receptor (EGFR), MET, and KIT were chosen in a proof-of-concept study. Their intracellular domains were inserted into a series of expression vectors encoding artificial TMDs, and they were tested for autophosphorylation activity in transient transfection assays. Active constructs could be identified for MET and EGFR, but not for KIT. Rat1 cell pools were generated expressing the MET or EGFR constructs, and their sensitivity to reference tool compounds was compared to that of MKN-45 or A431 cells. A good correlation between natural and recombinant cells led us to build a panel of clinically relevant MET mutant cell pools, based on the wild-type construct, which were then profiled via MET autophosphorylation and soft agar assays. In summary, a platform was established that allows for the rapid generation of cellular models for RTKs and their resistance mutants.
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20
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Bubici C, Papa S. JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol 2014; 171:24-37. [PMID: 24117156 DOI: 10.1111/bph.12432] [Citation(s) in RCA: 273] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 09/09/2013] [Accepted: 09/13/2013] [Indexed: 12/17/2022] Open
Abstract
The JNKs are master protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNKs is involved in cancer development and progression. Therefore, JNKs represent attractive targets for therapeutic intervention with small molecule kinase inhibitors. However, evidence supportive of a tumour suppressor role for the JNK proteins has also been documented. Recent studies showed that the two major JNK proteins, JNK1 and JNK2, have distinct or even opposing functions in different types of cancer. As such, close consideration of which JNK proteins are beneficial targets and, more importantly, what effect small molecule inhibitors of JNKs have on physiological processes, are essential. A number of ATP-competitive and ATP-non-competitive JNK inhibitors have been developed, but have several limitations such as a lack of specificity and cellular toxicity. In this review, we summarize the accumulating evidence supporting a role for the JNK proteins in the pathogenesis of different solid and haematological malignancies, and discuss many challenges and scientific opportunities in the targeting of JNKs in cancer.
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Affiliation(s)
- Concetta Bubici
- Section of Inflammation and Signal Transduction, Department of Medicine, Imperial College, London, UK; Biosciences Division, School of Health Sciences and Social Care, Brunel University, London, UK
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21
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Kitanaka C, Sato A, Okada M. JNK Signaling in the Control of the Tumor-Initiating Capacity Associated with Cancer Stem Cells. Genes Cancer 2014; 4:388-96. [PMID: 24349636 DOI: 10.1177/1947601912474892] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Deregulation of c-Jun NH2-terminal kinase (JNK) signaling occurs frequently in a variety of human cancers, yet the exact role(s) of JNK deregulation in cancer cell biology remains to be fully elucidated. Our recent demonstration that the activity of JNK is required not only for self-renewal of glioma stem cells but also for their tumor initiation has, however, identified a new role for JNK in the control of the stemness and tumor-initiating capacity of cancer cells. Significantly, transient JNK inhibition was sufficient to cause sustained loss of the tumor-initiating capacity of glioma stem cells, suggesting that the phenotype of "lost tumor-initiating capacity" may be as stable as the differentiated state and that the tumor-initiating capacity might therefore be under the control of JNK through an epigenetic mechanism that also governs stemness and differentiation. Here, in this article, we review the role and mechanism of JNK in the control of this "stemness-associated tumor-initiating capacity" (STATIC), a new hypothetical concept we introduce in this review article. Since the idea of STATIC is essentially applicable to both cancer types that do and do not follow the cancer stem cell hypothesis, we also give consideration to the possible involvement of JNK-mediated control of STATIC in a wide range of human cancers in which JNK is aberrantly activated. Theoretically, successful targeting of STATIC through JNK could contribute to long-term control of cancer. Issues to be considered before clinical application of therapies targeting this JNK-STATIC axis are also discussed.
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Affiliation(s)
- Chifumi Kitanaka
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan ; Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata, Japan ; Global Center of Excellence (COE) Program for Medical Sciences, Japan Society for the Promotion of Science, Tokyo, Japan
| | - Atsushi Sato
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan ; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan
| | - Masashi Okada
- Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan
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22
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Orgaz JL, Herraiz C, Sanz-Moreno V. Rho GTPases modulate malignant transformation of tumor cells. Small GTPases 2014; 5:e29019. [PMID: 25036871 DOI: 10.4161/sgtp.29019] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Rho GTPases are involved in the acquisition of all the hallmarks of cancer, which comprise 6 biological capabilities acquired during the development of human tumors. The hallmarks include proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis programs, as defined by Hanahan and Weinberg. (1) Controlling these hallmarks are genome instability and inflammation. Emerging hallmarks are reprogramming of energy metabolism and evading immune destruction. To give a different view to the readers, we will not be focusing on invasion, metastasis, or cytoskeletal remodeling, but we will review here how Rho GTPases contribute to other hallmarks of cancer with a special emphasis on malignant transformation.
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Affiliation(s)
- Jose L Orgaz
- Randall Division of Cell and Molecular Biophysics; New Hunt's House; Guy's Campus; King's College London; London, UK
| | - Cecilia Herraiz
- Randall Division of Cell and Molecular Biophysics; New Hunt's House; Guy's Campus; King's College London; London, UK
| | - Victoria Sanz-Moreno
- Randall Division of Cell and Molecular Biophysics; New Hunt's House; Guy's Campus; King's College London; London, UK
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Roles of the Nucleoporin Tpr in Cancer and Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 773:309-22. [DOI: 10.1007/978-1-4899-8032-8_14] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Chakraborty S, Chopra P, Hak A, Dastidar SG, Ray A. Hepatocyte growth factor is an attractive target for the treatment of pulmonary fibrosis. Expert Opin Investig Drugs 2013; 22:499-515. [PMID: 23484858 DOI: 10.1517/13543784.2013.778972] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Pulmonary fibrosis (PF) is a progressive fatal disorder and is characterized by alveolar epithelial injury, myofibroblast proliferation, and extracellular matrix remodeling, resulting in irreversible distortion of lung's architecture. Available therapies are associated with side effects and show restricted efficacy. Therefore, there is an urgent need to find a therapeutic solution to PF. Therapeutic strategies interfering myofibroblast expansion, apoptosis of epithelial and endothelial cells might be beneficial for treatment of PF. Hepatocyte growth factor (HGF), a pleiotropic growth factor, plays an important role in lung development, inflammation, repair, and regeneration. In animal model of PF, administration of recombinant HGF protein or ectopic HGF expression ameliorates fibrosis. AREAS COVERED The focus of this review is to highlight HGF as a promising therapeutic approach for the treatment of PF. The review discusses the currently available treatment option for PF as well as highlights the possible beneficial effect of HGF as a drug target. EXPERT OPINION HGF with its anti-fibrotic effect provides a promising new therapeutic approach by protecting lung from fibrotic remodeling and also promoting normal regeneration of lung. The development of HGF mimetics may provide a potential attractive therapy for treatment of this devastating and complex disease.
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Affiliation(s)
- Sushmita Chakraborty
- Daiichi Sankyo Life Science Research Centre in India (RCI), Department of Biology, Haryana, India
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25
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Qin X, Zheng S, Liu T, Liu Q, Liang M, Li X, Sheyhidin I, Lu X. Roles of phosphorylated JNK in esophageal squamous cell carcinomas of Kazakh ethnic. Mol Carcinog 2013; 53:526-36. [PMID: 23359384 DOI: 10.1002/mc.22004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 12/09/2012] [Accepted: 12/18/2012] [Indexed: 11/11/2022]
Abstract
The c-Jun NH2 -terminal kinase (JNK) signal pathway has been implicated in the growth, cellular proliferation, and apoptosis in many kinds of carcinomas. However, the role of JNK in the development of esophageal squamous cell carcinomas (ESCCs) is unknown. To investigate the role of JNK in ESCC, in vitro, esophageal cancer cell line Eca109 was pretreated using SP600125, JNK specific inhibitor, then was subjected to MTT assay to examine cellular proliferation, flow cytometric analysis to detect apoptosis and cell cycle, and wound healing assay to evaluate cell migration. Meanwhile, the mRNA and protein expression of JNK in Eca109 cells pretreated with SP600125 were examined by real-time quantitative reverse transcription PCR (qRT-PCR) and Western blotting, respectively. In vivo, 12 paired of fresh ESCC and normal adjacent tissues (NAT) from Kazakh patients were used to validate the expression of JNK by qRT-PCR and Western blotting. Furthermore, to reconfirm the expression trend of activation JNK (p-JNK), enlarged 72 paired of Kazakh's ESCC and NAT were subjected to immunohistochemistry. Our results showed that the suppression of p-JNK could lead to apoptosis and reduce proliferation in Eca109 cells. However, there was an elevated expression of p-JNK protein in NAT compared with ESCC tissues, and there was significant difference between p-JNK expression and pathological differentiation (P < 0.05) in Kazakh populations. Together, all the data we obtained in the present study indicated that the p-JNK MAPK pathway was involved in pathogenesis of Kazakh's ESCC, and played a different roles in carcinogenesis and development of Kazakh's ESCC.
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Affiliation(s)
- Xu Qin
- Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, P.R., China; State Key Lab Incubation Base of Xinjiang Major Diseases Research, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, P.R., China
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Mashima T, Seimiya H, Chen Z, Kataoka S, Tsuruo T. Apoptosis resistance in tumor cells. Cytotechnology 2012; 27:293-308. [PMID: 19002800 DOI: 10.1023/a:1008058031511] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Various antitumor agents induce apoptotic cell death in tumor cells. Since the apoptosis program in tumor cells plays a critical role in the chemotherapy-induced tumor cell killing, it is suggested that the defect in the signaling pathway of apoptosis could cause a new form of multidrug resistance in tumor cells. This article describes the recent findings concerning the mechanisms of chemotherapy-induced apoptosis and discusses the implication of apoptosis resistance in cancer chemotherapy.
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Affiliation(s)
- T Mashima
- Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113, Japan
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27
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Steinman RA, Brufsky AM, Oesterreich S. Zoledronic acid effectiveness against breast cancer metastases - a role for estrogen in the microenvironment? Breast Cancer Res 2012; 14:213. [PMID: 23014660 PMCID: PMC4053096 DOI: 10.1186/bcr3223] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Zoledronic acid (ZA) is an imidazole-containing bisphosphonate that has been extensively studied as an osteoclast inhibitor. ZA decreases bone turnover and has been effective in limiting osteolysis in metastatic cancers, including breast cancer. Recent clinical trials that demonstrated enhancement of disease-free survival by bisphosphonates have prompted interest in bisphosphonates as anti-cancer agents. ZA, for example, increased disease-free survival in postmenopausal and in premenopausal, hormone-suppressed breast cancer patients. Intriguingly, however, there was a lack of an anti-cancer effect of ZA in premenopausal women without ovarian suppression. These observations have prompted the conjecture that anti-cancer effects of ZA are limited to estrogen-poor environments. This review explores possible mechanisms compatible with differences in ZA activity in premenopausal women compared with postmenopausal (or hormone-suppressed) women.
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Abstract
c-MET is a receptor tyrosine kinase that, after binding with its ligand, hepatocyte growth factor, activates a wide range of different cellular signaling pathways, including those involved in proliferation, motility, migration and invasion. Although c-MET is important in the control of tissue homeostasis under normal physiological conditions, it has also been found to be aberrantly activated in human cancers via mutation, amplification or protein overexpression. This paper provides an overview of the c-MET signaling pathway, including its role in the development of cancers, and provides a rationale for targeting the pathway as a possible treatment option.
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Progress in cancer therapy targeting c-Met signaling pathway. Arch Pharm Res 2012; 35:595-604. [DOI: 10.1007/s12272-012-0402-6] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2011] [Revised: 11/13/2011] [Accepted: 11/19/2011] [Indexed: 01/09/2023]
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Felici A, Giubellino A, Bottaro DP. Gab1 mediates hepatocyte growth factor-stimulated mitogenicity and morphogenesis in multipotent myeloid cells. J Cell Biochem 2011; 111:310-21. [PMID: 20506405 DOI: 10.1002/jcb.22695] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hepatocyte growth factor (HGF)-stimulated mitogenesis, motogenesis and morphogenesis in various cell types begins with activation of the Met receptor tyrosine kinase and the recruitment of intracellular adaptors and kinase substrates. The adapter protein Gab1 is a critical effector and substrate of activated Met, mediating morphogenesis, among other activities, in epithelial cells. To define its role downstream of Met in hematopoietic cells, Gab1 was expressed in the HGF-responsive, Gab1-negative murine myeloid cell line 32D. Interestingly, the adhesion and motility of Gab1-expressing cells were significantly greater than parental cells, independent of growth factor treatment. Downstream of activated Met, Gab1 expression was specifically associated with rapid Shp-2 recruitment and activation, increased mitogenic potency, suppression of GATA-1 expression and concomitant upregulation of GATA-2 transcription. In addition to enhanced proliferation, continuous culture of Gab1-expressing 32D cells in HGF resulted in cell attachment, filopodia extension and phenotypic changes suggestive of monocytic differentiation. Our results suggest that in myeloid cells, Gab1 is likely to enhance HGF mitogenicity by coupling Met to Shp-2 and GATA-2 expression, thereby potentially contributing to normal myeloid differentiation as well as oncogenic transformation.
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Affiliation(s)
- Angelina Felici
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National, Institutes of Health, Bethesda, Maryland 20892-1501, USA
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31
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MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 2010; 11:834-48. [PMID: 21102609 DOI: 10.1038/nrm3012] [Citation(s) in RCA: 934] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.
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32
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Nitta RT, Del Vecchio CA, Chu AH, Mitra SS, Godwin AK, Wong AJ. The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis. Oncogene 2010; 30:234-44. [PMID: 20871632 DOI: 10.1038/onc.2010.414] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase family and have been implicated in tumorigenesis. One isoform in particular, JNK2α, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes and to increase tumor formation in mice. As JNK is frequently activated in non-small cell lung carcinoma (NSCLC), we investigated the role of the JNK2α isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered that 60% of the tested primary NSCLC tumors had three-fold higher JNK2 protein and two- to three-fold higher JNK2α mRNA expression than normal lung control tissue. To determine the importance of JNK2α in NSCLC progression, we reduced JNK2α expression in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2α had decreased cellular growth and anchorage-independent growth, and the tumors were four-fold smaller in mass. To elucidate the mechanism by which JNK2α induces NSCLC growth, we analyzed the JNK substrate, signal transducer and activator of transcription 3 (STAT3). Our data demonstrates for the first time that JNK2α can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue, thereby regulating the expression of oncogenic genes, such as c-Myc. Furthermore, reintroduction of JNK2α2 or STAT3 restored the tumorigenicity of the NSCLC cells, demonstrating that JNK2α is important for NSCLC progression. Our studies reveal a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2α.
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Affiliation(s)
- R T Nitta
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
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33
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Chen P, O'Neal JF, Ebelt ND, Cantrell MA, Mitra S, Nasrazadani A, Vandenbroek TL, Heasley LE, Van Den Berg CL. Jnk2 effects on tumor development, genetic instability and replicative stress in an oncogene-driven mouse mammary tumor model. PLoS One 2010; 5:e10443. [PMID: 20454618 PMCID: PMC2862739 DOI: 10.1371/journal.pone.0010443] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2009] [Accepted: 04/08/2010] [Indexed: 02/08/2023] Open
Abstract
Oncogenes induce cell proliferation leading to replicative stress, DNA damage and genomic instability. A wide variety of cellular stresses activate c-Jun N-terminal kinase (JNK) proteins, but few studies have directly addressed the roles of JNK isoforms in tumor development. Herein, we show that jnk2 knockout mice expressing the Polyoma Middle T Antigen transgene developed mammary tumors earlier and experienced higher tumor multiplicity compared to jnk2 wildtype mice. Lack of jnk2 expression was associated with higher tumor aneuploidy and reduced DNA damage response, as marked by fewer pH2AX and 53BP1 nuclear foci. Comparative genomic hybridization further confirmed increased genomic instability in PyV MT/jnk2−/− tumors. In vitro, PyV MT/jnk2−/− cells underwent replicative stress and cell death as evidenced by lower BrdU incorporation, and sustained chromatin licensing and DNA replication factor 1 (CDT1) and p21Waf1 protein expression, and phosphorylation of Chk1 after serum stimulation, but this response was not associated with phosphorylation of p53 Ser15. Adenoviral overexpression of CDT1 led to similar differences between jnk2 wildtype and knockout cells. In normal mammary cells undergoing UV induced single stranded DNA breaks, JNK2 localized to RPA (Replication Protein A) coated strands indicating that JNK2 responds early to single stranded DNA damage and is critical for subsequent recruitment of DNA repair proteins. Together, these data support that JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms.
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Affiliation(s)
- Peila Chen
- Division of Pharmacology and Toxicology, Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America
| | - Jamye F. O'Neal
- Division of Pharmacology and Toxicology, Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America
| | - Nancy D. Ebelt
- Institute of Cellular and Molecular Biology, School of Biological Sciences, The University of Texas at Austin, Austin, Texas, United States of America
| | - Michael A. Cantrell
- Institute of Cellular and Molecular Biology, School of Biological Sciences, The University of Texas at Austin, Austin, Texas, United States of America
| | - Shreya Mitra
- Division of Pharmacology and Toxicology, Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America
| | - Azadeh Nasrazadani
- Division of Pharmacology and Toxicology, Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America
| | - Tracy L. Vandenbroek
- Division of Pharmacology and Toxicology, Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America
| | - Lynn E. Heasley
- Department of Craniofacial Biology, University of Colorado Denver Anshutz Medical Campus, Aurora, Colorado, United States of America
| | - Carla L. Van Den Berg
- Division of Pharmacology and Toxicology, Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America
- * E-mail:
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Wang J, Kuiatse I, Lee AV, Pan J, Giuliano A, Cui X. Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation. Mol Cancer Res 2010; 8:266-77. [PMID: 20145041 DOI: 10.1158/1541-7786.mcr-09-0221] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The c-Jun NH(2)-terminus kinase (JNK) mediates stress-induced apoptosis and the cytotoxic effect of anticancer therapies. Paradoxically, recent clinical studies indicate that elevated JNK activity in human breast cancer is associated with poor prognosis. Here, we show that overexpression of a constitutively active JNK in human breast cancer cells did not cause apoptosis, but actually induced cell migration and invasion, a morphologic change associated with epithelial-mesenchymal transition (EMT), expression of mesenchymal-specific markers vimentin and fibronectin, and activity of activator protein transcription factors. Supporting this observation, mouse mammary tumor cells that have undergone EMT showed upregulated JNK activity, and the EMT was reversed by JNK inhibition. Sustained JNK activity enhanced insulin receptor substrate-2-mediated ERK activation, which in turn increased c-Fos expression and activator protein activity. In addition, hyperactive JNK attenuated the apoptosis of breast cancer cells treated by the chemotherapy drug paclitaxel, which is in contrast to the requirement for inducible JNK activity in response to cytotoxic chemotherapy. Blockade of extracellular signal-regulated kinase activity diminished hyperactive JNK-induced cell invasion and survival. Our data suggest that the role of JNK changes when its activity is elevated persistently above the basal levels associated with cell apoptosis, and that JNK activation may serve as a marker of breast cancer progression and resistance to cytotoxic drugs.
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Affiliation(s)
- Jinhua Wang
- Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA
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35
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Bertotti A, Burbridge MF, Gastaldi S, Galimi F, Torti D, Medico E, Giordano S, Corso S, Rolland-Valognes G, Lockhart BP, Hickman JA, Comoglio PM, Trusolino L. Only a Subset of Met-Activated Pathways Are Required to Sustain Oncogene Addiction. Sci Signal 2009; 2:ra80. [DOI: 10.1126/scisignal.2000643] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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36
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A selective small-molecule inhibitor of c-Jun N-terminal kinase 1. FEBS Lett 2009; 583:2208-12. [PMID: 19527717 DOI: 10.1016/j.febslet.2009.06.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Revised: 06/01/2009] [Accepted: 06/03/2009] [Indexed: 11/21/2022]
Abstract
Indiscriminately suppressing total c-Jun N-terminal kinase (JNK) activity is not an appropriate strategy because each JNK appears to have a distinct function in cancer, asthma, diabetes, or Parkinson's disease. Herein, we report that 7-(6-N-phenylaminohexyl)amino-2H-anthra[1,9-cd]pyrazol-6-one (AV-7) inhibited JNK1 activity, but not JNK2 or JNK3. We found that ultraviolet B (UVB) induced c-Jun phosphorylation and sub-G1 accumulation in JNK2(-/-) murine embryonic fibroblasts, which contain an abundance of JNK1, but not JNK2. These results demonstrate that AV-7 is an isoform selective small-molecule inhibitor of JNK1 activity, which might be developed as a therapeutic against diabetes.
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37
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Lin ML, Chung JG, Lu YC, Yang CY, Chen SS. Rhein inhibits invasion and migration of human nasopharyngeal carcinoma cells in vitro by down-regulation of matrix metalloproteinases-9 and vascular endothelial growth factor. Oral Oncol 2008; 45:531-7. [PMID: 18804415 DOI: 10.1016/j.oraloncology.2008.07.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2008] [Revised: 06/05/2008] [Accepted: 07/18/2008] [Indexed: 01/01/2023]
Abstract
Progression of cancer invasion is believed to be dependent on the remodeling of extracellular matrix induced by tumor cells. Rhein has been shown to inhibit the growth and proliferation of human nasopharyngeal carcinoma (NPC) cells. However, the molecular mechanism underlying rhein-induced inhibition of cancer invasion has not been explored. Herein, we show that rhein could inhibit the invasion and migration of NPC cells in vitro. Rhein inhibits invasion by reducing the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF). Moreover, we demonstrate that the pathway involved in rhein-inhibited invasion is presumably through the growth factor receptor bound protein 2/son of sevenless-Ras-mitogen-activated protein kinase (GRB2/SOS-Ras-MAPK) pathway, as shown by an decrease in the expression levels of GRB2, SOS-1 and Ras as well as led to suppression of the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK. Further study has shown that rhein also inhibited activation of transcription factor nuclear factor kappaB (NF-kappaB), which is known to implicate the regulation of MMP-9 and VEGF gene expression in cancer invasion. Our findings suggest that rhein inhibits the invasion of NPC cells may be mediated in part through the suppression of MMP-9 and VEGF expression via the modulation of NF-kappaB signaling pathway.
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Affiliation(s)
- Meng-Liang Lin
- Department of Medical Laboratory Science and Biotechnology, China Medical University, 91 Hsueh-Shih Road, Taichung, Taiwan, ROC
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38
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Shibata W, Maeda S, Hikiba Y, Yanai A, Sakamoto K, Nakagawa H, Ogura K, Karin M, Omata M. c-Jun NH2-terminal kinase 1 is a critical regulator for the development of gastric cancer in mice. Cancer Res 2008; 68:5031-9. [PMID: 18593901 DOI: 10.1158/0008-5472.can-07-6332] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
c-Jun NH(2)-terminal kinase (JNK) links several cellular processes, including proliferation and survival, and is believed to be involved in carcinogenesis. However, the role of JNK in gastric tumorigenesis is unknown. Immunohistochemical analysis reveals that JNK is frequently activated in human gastric cancer tissue. We investigated whether JNK1, a major JNK isozyme, is involved in chemically induced gastric cancer development. Mice lacking JNK1 exhibited a marked decrease in gastric carcinogenesis induced by N-methyl-N-nitrosourea, relative to their wild-type counterparts. Impaired tumor development correlated with decreased tumor initiation, which is associated with the production of reactive oxygen species. We also found that lower levels of tumorigenesis were correlated with the decreased expression of cyclin D and CDK as well as decreased cell proliferation. Taken together, JNK seems to be involved in both tumor initiation and promotion and may be an attractive target for the prevention of gastric carcinogenesis.
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Affiliation(s)
- Wataru Shibata
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Chiyoda-ku, Tokyo, Japan
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39
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Knudsen BS, Vande Woude G. Showering c-MET-dependent cancers with drugs. Curr Opin Genet Dev 2008; 18:87-96. [PMID: 18406132 DOI: 10.1016/j.gde.2008.02.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Accepted: 02/05/2008] [Indexed: 11/18/2022]
Abstract
The receptor tyrosine kinase, c-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) have become leading candidates for targeted cancer therapies. Inappropriate c-MET signaling through autocrine, paracrine, amplification, and mutational activation occurs in virtually all types of solid tumors (http://www.vai.org/met), contributing to one or a combination of proliferative, invasive, survival, or angiogenic cancer phenotypes. c-MET and HGF/SF participate in all stages of malignant progression and represent promising drug targets in a variety of cancer types, including carcinomas, sarcomas, and brain tumors. While many are in pre-clinical testing, a few inhibitors have entered clinical trials. With hundreds of thousands of potential responding cancers that express c-MET, the interest in this molecule as a drug target is not surprising. However, the cognate c-MET diagnostic tests lag behind. In addition, despite the great enthusiasm based on response rates in phase I trials, there is a need for caution. It is almost without question that combination therapies with c-MET-HGF/SF inhibitors will be required for most cancers to achieve a cytotoxic tumor response.
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Affiliation(s)
- Beatrice S Knudsen
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, Seattle, WA 98109, United States
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40
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Yao K, Cho YY, Bergen HR, Madden BJ, Choi BY, Ma WY, Bode AM, Dong Z. Nuclear factor of activated T3 is a negative regulator of Ras-JNK1/2-AP-1 induced cell transformation. Cancer Res 2007; 67:8725-35. [PMID: 17875713 DOI: 10.1158/0008-5472.can-06-4788] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The c-jun-NH(2)-kinases (JNK) play a critical role in tumor promoter-induced cell transformation and apoptosis. Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif. The transactivation domain of NFAT3 is found between amino acids (aa) 113 and 260 and includes the phosphorylation targets of JNK1 and JNK2. NFAT3 transactivation activity was suppressed in JNK1(-/-) or JNK2(-/-) mouse embryonic fibroblast (MEF) cells compared with wild-type MEF cells. Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose-dependent manner by JNK1 or JNK2. Double mutations at Ser(213) and Ser(217) suppressed NFAT3 transactivation activity; and SP600125, a JNK inhibitor, suppressed NFAT3-induced 3xNFAT-luciferase activity. Knockdown of JNK1 or JNK2 suppressed foci formation in NIH3T3 cells. Importantly, ectopic expression of NFAT3 inhibited AP-1 activity and suppressed foci formation. Furthermore, knockdown of NFAT3 enhanced Ras-JNK1 or JNK2-induced foci formation in NIH3T3 cells. Taken together, these results provided direct evidence for the anti-oncogenic potential of the NFAT3 transcription factor.
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Affiliation(s)
- Ke Yao
- Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA
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41
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Yang H, Magilnick N, Xia M, Lu SC. Effects of hepatocyte growth factor on glutathione synthesis, growth, and apoptosis is cell density-dependent. Exp Cell Res 2007; 314:398-412. [PMID: 17950727 DOI: 10.1016/j.yexcr.2007.09.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2007] [Revised: 09/10/2007] [Accepted: 09/24/2007] [Indexed: 12/22/2022]
Abstract
Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen that exerts opposing effects depending on cell density. Glutathione (GSH) is the main non-protein thiol in mammalian cells that modulates growth and apoptosis. We previously showed that GSH level is inversely related to cell density of hepatocytes and is positively related to growth. Our current work examined whether HGF can modulate GSH synthesis in a cell density-dependent manner and how GSH in turn influence HGF's effects. We found HGF treatment of H4IIE cells increased cell GSH levels only under subconfluent density. The increase in cell GSH under low density was due to increased transcription of GSH synthetic enzymes. This correlated with increased protein levels and nuclear binding activities of c-Jun, c-Fos, p65, p50, Nrf1 and Nrf2 to the promoter region of these genes. HGF acts as a mitogen in H4IIE cells under low cell density and protects against tumor necrosis factor alpha (TNFalpha)-induced apoptosis by limiting JNK activation. However, HGF is pro-apoptotic under high cell density and exacerbates TNFalpha-induced apoptosis by potentiating JNK activation. The increase in cell GSH under low cell density allows HGF to exert its full mitogenic effect but is not necessary for its anti-apoptotic effect.
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Affiliation(s)
- Heping Yang
- Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA 90033, USA
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42
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Wang L, Zhang Y, Li H, Xu Z, Santella RM, Weinstein IB. Hint1 inhibits growth and activator protein-1 activity in human colon cancer cells. Cancer Res 2007; 67:4700-8. [PMID: 17510397 DOI: 10.1158/0008-5472.can-06-4645] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
There is accumulating evidence that histidine triad (HIT) nucleotide-binding protein 1 (HINT1), a member of the evolutionary highly conserved HIT protein super family, is a novel tumor suppressor. However, the mechanism of action of HINT1 with respect to tumor suppression is not known. In the present study, we found that a series of human colon cancer cell lines displayed various levels of expression of HINT1, with a very low level in SW480 cells. This cell line also displayed partial methylation of the promoter region of the Hint1 gene, and treatment of these cells with 5-azadeoxycitidine increased expression of Hint1 mRNA and protein. Therefore, the decreased expression of HINT1 in SW480 cells seems to be due to epigenetic silencing. Increased expression of HINT1 in these cells, using a retrovirus vector (pLNCX2) that encodes either wild-type (WT) Hint1 or a point mutant (His(112)/Asn(112)) of Hint1, inhibited the proliferation of SW480 cells. Because of the important role of the activator protein-1 (AP-1) transcription factor in cancer cells, we examined possible effects of HINT1 on AP-1 transcription factor activity in SW480 cells transfected with an AP-1-luciferase reporter. We found that cotransfection with a pHA-Hint1 plasmid DNA significantly inhibited this activity. Studies with inhibitors indicated that AP-1 activity in SW480 cells requires the activity of c-Jun NH(2)-terminal kinase (JNK) 2 and not JNK1. Cotransfection with the Hint1 plasmid DNA also inhibited AP-1-luciferase reporter activity in WT mouse embryo fibroblast (MEF) studies, and studies with JNK1 deleted or JNK2 deleted MEFs confirmed the essential role for JNK2, but not JNK1, in mediating AP-1 activity. Recent studies indicate that the protein plenty of SH3 (POSH) provides a scaffold that enhances JNK activity. We found that cotransfection of a plasmid DNA encoding POSH stimulated the phosphorylation of c-Jun and also AP-1 reporter activity, and cotransfection with Hint1 inhibited both of these activities. Furthermore, coimmunoprecipitation studies provided evidence that HINT1 forms an in vivo complex with POSH and JNK. These results suggest that HINT1 inhibits AP-1 activity by binding to a POSH-JNK2 complex, thus inhibiting the phosphorylation of c-Jun. This effect could contribute to the tumor suppressor activity of HINT1.
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Affiliation(s)
- Lin Wang
- Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032-2704, USA
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43
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Abstract
Mitogen-activated protein (MAP) kinase kinase 4 (MKK4) is a component of stress activated MAP kinase signaling modules. It directly phosphorylates and activates the c-Jun N-terminal kinase (JNK) and p38 families of MAP kinases in response to environmental stress, pro-inflammatory cytokines and developmental cues. MKK4 is ubiquitously expressed and the targeted deletion of the Mkk4 gene in mice results in early embryonic lethality. Further studies in mice have indicated a role for MKK4 in liver formation, the immune system and cardiac hypertrophy. In humans, it is reported that loss of function mutations in the MKK4 gene are found in approximately 5% of tumors from a variety of tissues, suggesting it may have a tumor suppression function. Furthermore, MKK4 has been identified as a suppressor of metastasis of prostate and ovarian cancers. However, the role of MKK4 in cancer development appears complex as other studies support a pro-oncogenic role for MKK4 and JNK. Here we review the biochemical and functional properties of MKK4 and discuss the likely mechanisms by which it may regulate the steps leading to the formation of cancers.
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Affiliation(s)
- A J Whitmarsh
- Faculty of Life Sciences, University of Manchester, Manchester, UK
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Vivanco I, Palaskas N, Tran C, Finn SP, Getz G, Kennedy NJ, Jiao J, Rose J, Xie W, Loda M, Golub T, Mellinghoff IK, Davis RJ, Wu H, Sawyers CL. Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell 2007; 11:555-69. [PMID: 17560336 DOI: 10.1016/j.ccr.2007.04.021] [Citation(s) in RCA: 199] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2006] [Revised: 02/14/2007] [Accepted: 04/30/2007] [Indexed: 11/30/2022]
Abstract
Although most oncogenic phenotypes of PTEN loss are attributed to AKT activation, AKT alone is not sufficient to induce all of the biological activities associated with PTEN inactivation. We searched for additional PTEN-regulated pathways through gene set enrichment analysis (GSEA) and identified genes associated with JNK activation. PTEN null cells exhibit higher JNK activity, and genetic studies demonstrate that JNK functions parallel to and independently of AKT. Furthermore, PTEN deficiency sensitizes cells to JNK inhibition and negative feedback regulation of PI3K was impaired in PTEN null cells. Akt and JNK activation are highly correlated in human prostate cancer. These findings implicate JNK in PI3K-driven cancers and demonstrate the utility of GSEA to identify functional pathways using genetically defined systems.
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Affiliation(s)
- Igor Vivanco
- Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA
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Sánchez-Tilló E, Comalada M, Xaus J, Farrera C, Valledor AF, Caelles C, Lloberas J, Celada A. JNK1 Is Required for the Induction of Mkp1 Expression in Macrophages during Proliferation and Lipopolysaccharide-dependent Activation. J Biol Chem 2007; 282:12566-73. [PMID: 17337450 DOI: 10.1074/jbc.m609662200] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Macrophages proliferate in the presence of their growth factor, macrophage colony-stimulating factor (M-CSF), in a process that is dependent on early and short ERK activation. Lipopolysaccharide (LPS) induces macrophage activation, stops proliferation, and delays ERK phosphorylation, thereby triggering an inflammatory response. Proliferating or activating responses are balanced by the kinetics of ERK phosphorylation, the inactivation of which correlates with Mkp1 induction. Here we show that the transcriptional induction of this phosphatase by M-CSF or LPS depends on JNK but not on the other MAPKs, ERK and p38. The lack of Mkp1 induction caused by JNK inhibition prolonged ERK-1/2 and p38 phosphorylation. The two JNK genes, jnk1 and jnk2, are constitutively expressed in macrophages. However, only the JNK1 isoform was phosphorylated and, as determined in single knock-out mice, was necessary for Mkp1 induction by M-CSF or LPS. JNK1 was also required for pro-inflammatory cytokine biosynthesis (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) and LPS-induced NO production. This requirement is independent of Mkp1 expression, as shown in Mkp1 knock-out mice. Our results demonstrate a critical role for JNK1 in the regulation of Mkp1 induction and in LPS-dependent macrophage activation.
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Affiliation(s)
- Ester Sánchez-Tilló
- Institute for Research in Biomedicine and University of Barcelona, Barcelona Science Park, Josep Samitier 1-5, E-08028 Barcelona, Spain
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Shida Y, Igawa T, Hakariya T, Sakai H, Kanetake H. p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion. Biochem Biophys Res Commun 2007; 353:744-9. [PMID: 17196171 DOI: 10.1016/j.bbrc.2006.12.077] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2006] [Accepted: 12/13/2006] [Indexed: 11/27/2022]
Abstract
Increased levels of serum interleukin-6 (IL-6) are frequently observed in patients with advanced, hormone-refractory prostate cancer. However, the precise mechanism of IL-6 regulation is still largely unknown. Since prostate cancer gradually progresses to an androgen-independent state despite the stress caused by various therapeutic agents, we hypothesized the stress-activated protein kinases (SAPKs) involvement in androgen-independent growth or IL-6 secretion of prostate cancer cells. Using PC-3 and DU145 human prostate cancer cells, we analyzed the role of SAPKs in IL-6 mediated cell growth and found that the p38MAPK and JNK are involved in androgen-independent cancer cell growth. Furthermore, IL-6 secretion by PC-3 and DU145 cells was significantly suppressed by SAPKs inhibitor, especially by p38MAPK inhibitor SB203580, but not by JNK inhibitor SP600125 nor by MEK inhibitor, PD98059. These results raised the possibility that the IL-6 mediated androgen-independent proliferation of PC-3 and DU145 cells is regulated at least partly via SAPKs signaling pathway especially through p38MAPK activation.
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Affiliation(s)
- Yohei Shida
- Division of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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Tsai CL, Li HP, Lu YJ, Hsueh C, Liang Y, Chen CL, Tsao SW, Tse KP, Yu JS, Chang YS. Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. Cancer Res 2007; 66:11668-76. [PMID: 17178861 DOI: 10.1158/0008-5472.can-06-2194] [Citation(s) in RCA: 177] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
EBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH(2)-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IkappaB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor-associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor kappaB and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1.
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Affiliation(s)
- Chia-Lung Tsai
- Graduate Institute of Basic Medical Sciences and Pathology Core, Chang-Gung Molecular Medicine Research Center, Chang-Gung University, Taiwan, Republic of China
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Zinser GM, Leonis MA, Toney K, Pathrose P, Thobe M, Kader SA, Peace BE, Beauman SR, Collins MH, Waltz SE. Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation. Cancer Res 2007; 66:11967-74. [PMID: 17178895 DOI: 10.1158/0008-5472.can-06-2473] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Activated growth factor receptor tyrosine kinases (RTK) play pivotal roles in a variety of human cancers, including breast cancer. Ron, a member of the Met RTK proto-oncogene family, is overexpressed or constitutively active in 50% of human breast cancers. To define the significance of Ron overexpression and activation in vivo, we generated transgenic mice that overexpress a wild-type or constitutively active Ron receptor in the mammary epithelium. In these animals, Ron expression is significantly elevated in mammary glands and leads to a hyperplastic phenotype by 12 weeks of age. Ron overexpression is sufficient to induce mammary transformation in all transgenic animals and is associated with a high degree of metastasis, with metastatic foci detected in liver and lungs of >86% of all transgenic animals. Furthermore, we show that Ron overexpression leads to receptor phosphorylation and is associated with elevated levels of tyrosine phosphorylated beta-catenin and the up-regulation of genes, including cyclin D1 and c-myc, which are associated with poor prognosis in patients with human breast cancers. These studies suggest that Ron overexpression may be a causative factor in breast tumorigenesis and provides a model to dissect the mechanism by which the Ron induces transformation and metastasis.
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Affiliation(s)
- Glendon M Zinser
- Department of Surgery, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45267, USA
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Wang B, Tsukada J, Higashi T, Mizobe T, Matsuura A, Mouri F, Sawamukai N, Ra C, Tanaka Y. Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125. Genes Cells 2006; 11:983-92. [PMID: 16923120 DOI: 10.1111/j.1365-2443.2006.01005.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Activation of c-jun N-terminal kinase (JNK) through c-kit-mediated phosphatidylinositol 3 (PI3) and Src kinase pathways plays an important role in cell proliferation and survival in mast cells. Gain-of-function mutations in c-kit are found in several human neoplasms. Constitutive activation of c-kit has been observed in human mastocytosis and gastrointestinal stromal tumor. In the present study, we demonstrate that an anthrapyrazole SP600125, a reversible ATP-competitive inhibitor of JNK inhibits proliferation of human HMC-1 showed constitutive activation of JNK/c-Jun, and the inhibitory effect of SP600125 on cell proliferation was associated with cell cycle arrest at the G1 phase and apoptosis accompanied by the cleavage of caspase-3 and PARP. Caspase-3 inhibitor Z-DEVD-FMK almost completely inhibited SP600125-induced apoptosis of HMC-1 cells. In contrast, caspase-9 inhibitor Z-LEHD-FMK failed to block SP600125-induced apoptosis. Following Sp600125 treatment, down-regulation of cyclin D3 protein expression, but not p53 was also observed. Thus, JNK/c-Jun is essential for proliferation and survival of HMC-1 cells. The results obtained from the present study suggest the possibility that JNK/c-Jun may be a therapeutic target in diseases associated with mutations in the catalytic domain of c-kit.
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Affiliation(s)
- Bin Wang
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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Schmidt H, Hoffmann S, Tran T, Stoldt M, Stangler T, Wiesehan K, Willbold D. Solution structure of a Hck SH3 domain ligand complex reveals novel interaction modes. J Mol Biol 2006; 365:1517-32. [PMID: 17141806 DOI: 10.1016/j.jmb.2006.11.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2006] [Revised: 10/24/2006] [Accepted: 11/03/2006] [Indexed: 12/01/2022]
Abstract
We studied the interaction of hematopoietic cell kinase SH3 domain (HckSH3) with an artificial 12-residue proline-rich peptide PD1 (HSKYPLPPLPSL) identified as high affinity ligand (K(D)=0.2 muM). PD1 shows an unusual ligand sequence for SH3 binding in type I orientation because it lacks the typical basic anchor residue at position P(-3), but instead has a tyrosine residue at this position. A basic lysine residue, however, is present at position P(-4). The solution structure of the HckSH3:PD1 complex, which is the first HckSH3 complex structure available, clearly reveals that the P(-3) tyrosine residue of PD1 does not take the position of the typical anchor residue but rather forms additional van der Waals interactions with the HckSH3 RT loop. Instead, lysine at position P(-4) of PD1 substitutes the function of the P(-3) anchor residue. This finding expands the well known ligand consensus sequence +xxPpxP by +xxxPpxP. Thus, software tools like iSPOT fail to identify PD1 as a high-affinity HckSH3 ligand so far. In addition, a short antiparallel beta-sheet in the RT loop of HckSH3 is observed upon PD1 binding. The structure of the HckSH3:PD1 complex reveals novel features of SH3 ligand binding and yields new insights into the structural basics of SH3-ligand interactions. Consequences for computational prediction tools adressing SH3-ligand interactions as well as the biological relevance of our findings are discussed.
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Affiliation(s)
- Holger Schmidt
- Forschungszentrum Jülich GmbH, INB, Biomolecular NMR, 52425 Jülich, Germany
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