Abstract
The aim of this study was to establish the role of serine/threonine protein phosphatase 2A (PP2A) in the survival of leukemic cells from patients with adult T cell leukemia (ATL), associated with human T cell leukemia virus type 1 (HTLV-1). In HTLV-1-infected T cell lines and ATL cells, okadaic acid (OkA), a potent PP2A inhibitor, induced decrease in cell viability and G1 cell cycle arrest by decreasing the expression levels of cyclin D2, cyclin-dependent kinase 4 and cyclin-dependent kinase 6, phosphorylation of pRb, and upregulation of p21, p27 and GADD45α. OkA-induced apoptosis was also due to the suppression of expression of Bcl-2, Bcl-xL and XIAP, and the activation of caspases-3, -8 and -9, and caspase-3 downstream mammalian STE20-like kinase 1 and H2AX. OkA inhibited nuclear factor-kappa B DNA binding and activated mitogen-activated protein (MAP) kinases. Other new PP2A-specific inhibitors, cytostatin and rubratoxin A, also induced decrease in cell viability through caspase-dependent mechanism. MAP kinase inhibitors confirmed the role of p38 MAP kinase in PP2A inhibitors-induced apoptosis. OkA resulted in the generation of reactive oxygen species, and exogenous antioxidant prevented activation of the indicated caspases. Finally, PP2A knockdown inhibited cell growth. The results showed that PP2A inhibition caused reactive oxygen species generation and affected distinct signaling pathways, resulting in the activation of H2AX and subsequent apoptotic cell death. These results suggest that PP2A is a potentially useful target in the treatment of ATL.
Keywords: Adult T cell leukemia, H2AX, human T cell leukemia virus type 1, nuclear factor-kappa B, okadaic acid, protein phosphatase 2A, reactive oxygen species.
Current Cancer Drug Targets
Title:Protein Phosphatase 2A as a Potential Target for Treatment of Adult T Cell Leukemia
Volume: 13 Issue: 8
Author(s): Naoki Mori, Chie Ishikawa, Jun-Nosuke Uchihara and Takeshi Yasumoto
Affiliation:
Keywords: Adult T cell leukemia, H2AX, human T cell leukemia virus type 1, nuclear factor-kappa B, okadaic acid, protein phosphatase 2A, reactive oxygen species.
Abstract: The aim of this study was to establish the role of serine/threonine protein phosphatase 2A (PP2A) in the survival of leukemic cells from patients with adult T cell leukemia (ATL), associated with human T cell leukemia virus type 1 (HTLV-1). In HTLV-1-infected T cell lines and ATL cells, okadaic acid (OkA), a potent PP2A inhibitor, induced decrease in cell viability and G1 cell cycle arrest by decreasing the expression levels of cyclin D2, cyclin-dependent kinase 4 and cyclin-dependent kinase 6, phosphorylation of pRb, and upregulation of p21, p27 and GADD45α. OkA-induced apoptosis was also due to the suppression of expression of Bcl-2, Bcl-xL and XIAP, and the activation of caspases-3, -8 and -9, and caspase-3 downstream mammalian STE20-like kinase 1 and H2AX. OkA inhibited nuclear factor-kappa B DNA binding and activated mitogen-activated protein (MAP) kinases. Other new PP2A-specific inhibitors, cytostatin and rubratoxin A, also induced decrease in cell viability through caspase-dependent mechanism. MAP kinase inhibitors confirmed the role of p38 MAP kinase in PP2A inhibitors-induced apoptosis. OkA resulted in the generation of reactive oxygen species, and exogenous antioxidant prevented activation of the indicated caspases. Finally, PP2A knockdown inhibited cell growth. The results showed that PP2A inhibition caused reactive oxygen species generation and affected distinct signaling pathways, resulting in the activation of H2AX and subsequent apoptotic cell death. These results suggest that PP2A is a potentially useful target in the treatment of ATL.
Export Options
About this article
Cite this article as:
Mori Naoki, Ishikawa Chie, Uchihara Jun-Nosuke and Yasumoto Takeshi, Protein Phosphatase 2A as a Potential Target for Treatment of Adult T Cell Leukemia, Current Cancer Drug Targets 2013; 13 (8) . https://dx.doi.org/10.2174/156800961131300093
DOI https://dx.doi.org/10.2174/156800961131300093 |
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
-
Targeting the G2/M Transition for Antitumor Therapy
Letters in Drug Design & Discovery Central Nervous System Abnormalities in Fibromyalgia and Chronic Fatigue Syndrome: New Concepts in Treatment
Current Pharmaceutical Design Presenilin and γ -Secretase Activity: A Viable Therapeutic Target for Alzheimers Disease?
Current Signal Transduction Therapy Eph/Ephrin Signalling and Function in Oncogenesis: Lessons from Embryonic Development
Current Cancer Drug Targets Heat Shock Protein 90 Inhibitors as Therapeutic Agents
Recent Patents on Anti-Cancer Drug Discovery Natural Medicine:The Genus Angelica
Current Medicinal Chemistry Can γH2AX be Used to Personalise Cancer Treatment?
Current Molecular Medicine The Role of Mitochondria in Cancer Induction, Progression and Changes in Metabolism
Mini-Reviews in Medicinal Chemistry Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs
Pharmaceutical Nanotechnology Lysine Acetyltransferases CBP and p300 as Therapeutic Targets in Cognitive and Neurodegenerative Disorders
Current Pharmaceutical Design Pomegranate, its Components, and Modern Deliverable Formulations as Potential Botanicals in the Prevention and Treatment of Various Cancers
Current Drug Delivery Personalized Medicine in Oncology: A Personal View with Myths and Facts
Current Clinical Pharmacology Hepatic MicroRNA Orchestra: A New Diagnostic, Prognostic and Theranostic Tool for Hepatocarcinogenesis
Mini-Reviews in Medicinal Chemistry MicroRNAs in Chronic Lymphocytic Leukemia: An Old Disease with New Genetic Insights
MicroRNA Cationicity and Hydrophobicity Enhance the Cytotoxic Potency of Phoratoxin C Anticancer Peptide Analogues against Triple Negative Breast Cancer Cells
Current Bioactive Compounds The Role of Endogenous H2S in Cardiovascular Physiology
Current Pharmaceutical Biotechnology Artificial Intelligence for Epigenetics: Towards Personalized Medicine
Current Medicinal Chemistry Current Advances in Retroviral Gene Therapy
Current Gene Therapy The Role of the Tyrosine Kinase Inhibitor STI571 in the Treatment of Cancer
Current Cancer Drug Targets Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
Current Drug Metabolism