Abstract
Osteosarcoma (OS) is the most common primary malignancy of bone and is usually associated with poor prognosis due to its high incidence of metastasis and chemoresistance. Molecular pathogenesis of OS is poorly understood. We previously showed that OS cells are refractory to BMP9-induced osteogenesis and respond favorably to proliferation and tumor growth. Here we investigate if Notch signaling mediates the BMP9-promoted cell proliferation and tumor growth of human osteosarcoma (OS). We find that the expression of Notch1, Notch2, Notch3, DLL1, JAG1 and JAG2 is readily detected in most of the tested OS cell lines. BMP9-promoted OS cell proliferation, migration, and cell cycle S/G2 progression are effectively inhibited by a dominant-negative mutant of Notch1 (dnNotch1) or the γ-secretase inhibitor Compound E (ComE). Furthermore, BMP9-promoted tumor growth and osteolytic lesions in vivo are significantly inhibited by dnNotch1. BMP9 up-regulates the expression of Notch1, Notch3, DLL1, and JAG1 in OS cells. Accordingly, BMP9 stimulation induces a nuclear accumulation of NICD, which is blocked by ComE. Our results demonstrate that BMP9-promoted OS proliferation and tumor growth is at least in part mediated by Notch signaling, suggesting that osteogenic BMPs may function as upstream regulators of Notch signaling in OS tumorigenesis. Thus, pharmacologic intervention of Notch signaling may be explored as a new therapeutic strategy for human OS tumors.
Keywords: BMP9, bone tumorigenesis, notch signaling, osteogenesis, osteosarcoma, soft tissue tumors.
Current Cancer Drug Targets
Title:Targeting BMP9-Promoted Human Osteosarcoma Growth by Inactivation of Notch Signaling
Volume: 14 Issue: 3
Author(s): Hongmei Zhang, Zhong-Liang Deng, Tong-Chuan He, Rex C. Haydon, Hue H. Luu, Youlin Deng, Jixing Ye, Zhonglin Zhang, Wei Liu, Zhengjian Yan, Qian Zhang, Junhui Zhang, Zhan Liao, Guolin Zhou, Ruidong Li, Fang Deng, Sheng Wen, Xian Chen, Guoxin Nan, Ningning Wu, Ning Wang, Hongyu Zhang, Yang Wang, Liangjun Yin, Wei Shui, Jing Cui and Wenwen Zhang
Affiliation:
Keywords: BMP9, bone tumorigenesis, notch signaling, osteogenesis, osteosarcoma, soft tissue tumors.
Abstract: Osteosarcoma (OS) is the most common primary malignancy of bone and is usually associated with poor prognosis due to its high incidence of metastasis and chemoresistance. Molecular pathogenesis of OS is poorly understood. We previously showed that OS cells are refractory to BMP9-induced osteogenesis and respond favorably to proliferation and tumor growth. Here we investigate if Notch signaling mediates the BMP9-promoted cell proliferation and tumor growth of human osteosarcoma (OS). We find that the expression of Notch1, Notch2, Notch3, DLL1, JAG1 and JAG2 is readily detected in most of the tested OS cell lines. BMP9-promoted OS cell proliferation, migration, and cell cycle S/G2 progression are effectively inhibited by a dominant-negative mutant of Notch1 (dnNotch1) or the γ-secretase inhibitor Compound E (ComE). Furthermore, BMP9-promoted tumor growth and osteolytic lesions in vivo are significantly inhibited by dnNotch1. BMP9 up-regulates the expression of Notch1, Notch3, DLL1, and JAG1 in OS cells. Accordingly, BMP9 stimulation induces a nuclear accumulation of NICD, which is blocked by ComE. Our results demonstrate that BMP9-promoted OS proliferation and tumor growth is at least in part mediated by Notch signaling, suggesting that osteogenic BMPs may function as upstream regulators of Notch signaling in OS tumorigenesis. Thus, pharmacologic intervention of Notch signaling may be explored as a new therapeutic strategy for human OS tumors.
Export Options
About this article
Cite this article as:
Zhang Hongmei, Deng Zhong-Liang, He Tong-Chuan, Haydon C. Rex, Luu H. Hue, Deng Youlin, Ye Jixing, Zhang Zhonglin, Liu Wei, Yan Zhengjian, Zhang Qian, Zhang Junhui, Liao Zhan, Zhou Guolin, Li Ruidong, Deng Fang, Wen Sheng, Chen Xian, Nan Guoxin, Wu Ningning, Wang Ning, Zhang Hongyu, Wang Yang, Yin Liangjun, Shui Wei, Cui Jing and Zhang Wenwen, Targeting BMP9-Promoted Human Osteosarcoma Growth by Inactivation of Notch Signaling, Current Cancer Drug Targets 2014; 14 (3) . https://dx.doi.org/10.2174/1568009614666140305105805
DOI https://dx.doi.org/10.2174/1568009614666140305105805 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Potential MicroRNA Targets for Cancer Chemotherapy
Current Medicinal Chemistry From the Table to the Bedside: Can Food-Derived Sulforaphane be used as a Novel Agent to Treat Leukemia?
Current Cancer Drug Targets CD248: Reviewing its Role in Health and Disease
Current Drug Targets High-Content Analysis of Kinase Activity in Cells
Combinatorial Chemistry & High Throughput Screening Targeting the Eph System with Peptides and Peptide Conjugates
Current Drug Targets Combined Therapies of Bone Disease with Bisphosphonates
Current Pharmaceutical Design Formulation and In Vitro Evaluation of Gelatin Nanospheres for the Oral Delivery of Selegiline
Current Nanoscience Dual-Specificity MAP Kinase Phosphatases as Targets of Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry Hypoxic Regulation of Metastasis via Hypoxia-Inducible Factors
Current Molecular Medicine Nuclear Export as a Novel Therapeutic Target: The CRM1 Connection
Current Cancer Drug Targets Anti-Tumor Activity of Non-Nucleosidic Reverse Transcriptase Inhibitors
Current Pharmaceutical Design L1 Retrotransposon and Retinoblastoma: Molecular Linkages Between Epigenetics and Cancer
Current Molecular Medicine Co-opting Functions of Cholinesterases in Neural, Limb and Stem Cell Development
Protein & Peptide Letters Cancer Stem Cells: The ‘Achilles Heel’ of Chemo-Resistant Tumors
Recent Patents on Anti-Cancer Drug Discovery MicroRNAs Implications in the Onset, Diagnosis, and Prognosis of Osteosarcoma
Current Molecular Medicine Use of Anticancer Platinum Compounds in Combination Therapies and Challenges in Drug Delivery
Current Medicinal Chemistry Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation
Current Pharmacogenomics and Personalized Medicine Neurokinin-1 Receptor Antagonists as Anticancer Drugs
Letters in Drug Design & Discovery Clinical Applications and Biosafety of Human Adult Mesenchymal Stem Cells
Current Pharmaceutical Design Could Growth Factor-Mediated Extracellular Matrix Deposition and Degradation Offer the Ground for Directed Pharmacological Targeting in Fibrosarcoma?
Current Medicinal Chemistry