Abstract
In an effort to develop strategies that improve the efficacy of existing anticancer agents, we have conducted a siRNA-based RNAi screen to identify genes that, when targeted by siRNA, improve the activity of the topoisomerase I (Top1) poison camptothecin (CPT). Screening was conducted using a set of siRNAs corresponding to over 400 apoptosisrelated genes in MDA-MB-231 breast cancer cells. During the course of these studies, we identified the silencing of MAP3K7 as a significant enhancer of CPT activity. Follow-up analysis of caspase activity and caspase-dependent phosphorylation of histone H2AX demonstrated that the silencing of MAP3K7 enhanced CPT-associated apoptosis. Silencing MAP3K7 also sensitized cells to additional compounds, including CPT clinical analogs. This activity was not restricted to MDA-MB-231 cells, as the silencing of MAP3K7 also sensitized the breast cancer cell line MDA-MB-468 and HCT-116 colon cancer cells. However, MAP3K7 silencing did not affect compound activity in the comparatively normal mammary epithelial cell line MCF10A, as well as some additional tumorigenic lines. MAP3K7 encodes the TAK1 kinase, an enzyme that is central to the regulation of many processes associated with the growth of cancer cells (e.g. NF- κB, JNK, and p38 signaling). An analysis of TAK1 signaling pathway members revealed that the silencing of TAB2 also sensitizes MDA-MB-231 and HCT-116 cells towards CPT. These findings may offer avenues towards lowering the effective doses of Top1 inhibitors in cancer cells and, in doing so, broaden their application.
Keywords: RNAi, siRNA, Screen, Camptothecin, TAK1, MAP3K7, TAB2, TRAF6., ataxia telangiectasia mutated, H2AX, NF-κB essential modulator
Current Cancer Drug Targets
Title: RNAi Screening Identifies TAK1 as a Potential Target for the Enhanced Efficacy of Topoisomerase Inhibitors
Volume: 11 Issue: 8
Author(s): S. E. Martin, Z.-H. Wu, K. Gehlhaus, T. L. Jones, Y.-W. Zhang, R. Guha, S. Miyamoto, Y. Pommier and N. J. Caplen
Affiliation:
Keywords: RNAi, siRNA, Screen, Camptothecin, TAK1, MAP3K7, TAB2, TRAF6., ataxia telangiectasia mutated, H2AX, NF-κB essential modulator
Abstract: In an effort to develop strategies that improve the efficacy of existing anticancer agents, we have conducted a siRNA-based RNAi screen to identify genes that, when targeted by siRNA, improve the activity of the topoisomerase I (Top1) poison camptothecin (CPT). Screening was conducted using a set of siRNAs corresponding to over 400 apoptosisrelated genes in MDA-MB-231 breast cancer cells. During the course of these studies, we identified the silencing of MAP3K7 as a significant enhancer of CPT activity. Follow-up analysis of caspase activity and caspase-dependent phosphorylation of histone H2AX demonstrated that the silencing of MAP3K7 enhanced CPT-associated apoptosis. Silencing MAP3K7 also sensitized cells to additional compounds, including CPT clinical analogs. This activity was not restricted to MDA-MB-231 cells, as the silencing of MAP3K7 also sensitized the breast cancer cell line MDA-MB-468 and HCT-116 colon cancer cells. However, MAP3K7 silencing did not affect compound activity in the comparatively normal mammary epithelial cell line MCF10A, as well as some additional tumorigenic lines. MAP3K7 encodes the TAK1 kinase, an enzyme that is central to the regulation of many processes associated with the growth of cancer cells (e.g. NF- κB, JNK, and p38 signaling). An analysis of TAK1 signaling pathway members revealed that the silencing of TAB2 also sensitizes MDA-MB-231 and HCT-116 cells towards CPT. These findings may offer avenues towards lowering the effective doses of Top1 inhibitors in cancer cells and, in doing so, broaden their application.
Export Options
About this article
Cite this article as:
E. Martin S., Wu Z.-H., Gehlhaus K., L. Jones T., Zhang Y.-W., Guha R., Miyamoto S., Pommier Y. and J. Caplen N., RNAi Screening Identifies TAK1 as a Potential Target for the Enhanced Efficacy of Topoisomerase Inhibitors, Current Cancer Drug Targets 2011; 11 (8) . https://dx.doi.org/10.2174/156800911797264734
DOI https://dx.doi.org/10.2174/156800911797264734 |
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
-
P-Glycoprotein - Implications of Metabolism of Neoplastic Cells and Cancer Therapy
Current Cancer Drug Targets Reproductive Toxicology of Environmental Toxicants: Emerging Issues and Concerns
Current Pharmaceutical Design Tetracyclic Triterpenoids in Herbal Medicines and their Activities in Diabetes and its Complications
Current Topics in Medicinal Chemistry Anti Tumor Necrosis Factor-a Monoclonal Antibody (Infliximab) Therapy in Patients with Inflammatory Bowel Disease (IBD): Applications and Side Effects
Drug Design Reviews - Online (Discontinued) Evaluation of Hyperforin Analogues for Inhibition of 5-lipoxygenase
Medicinal Chemistry Targeting Negative Regulators of TRIF-dependent TLR Signaling Pathway as a Novel Therapeutic Strategy
Current Signal Transduction Therapy Pyrrolizines as Potential Anticancer Agents: Design, Synthesis, Caspase-3 activation and Micronucleus (MN) Induction
Anti-Cancer Agents in Medicinal Chemistry Editorial [ Hot Topic: Novel Medicinal Chemistry Approaches to New Anti-cancer Agents (Guest Editor: Diane H. Boschelli) ]
Current Topics in Medicinal Chemistry Modern Perspectives on the Structure, Function and Evolution of the Relaxin-Like Peptides and their Receptors
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Flavones as a Privileged Scaffold in Drug Discovery: Current Developments
Current Organic Synthesis (Section A: Molecular, Structural, and Cellular Biology of Drug Transporters) The Role of MDR1 Genetic Polymorphisms in Interindividual Variability in P-glycoprotein Expression and Function
Current Drug Metabolism Virus-Associated Vasculitides
Current Immunology Reviews (Discontinued) Immunomodulation in Inflammatory Neuropathies: Rationale and Safety
Current Drug Safety Editorial: [Recent Advances in Mammography]
Recent Patents on Medical Imaging The Role of Phospholipase D Enzyme(s) in Modulating Cell Signaling: Implications for Cancer Drug Development
Current Bioactive Compounds Melatonin as Antioxidant Under Pathological Processes
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Editorial (Thematic Issue: Applications of Peptides in Nanotechnology)
Current Topics in Medicinal Chemistry The Impact of Folate Status on the Efficacy of Colorectal Cancer Treatment
Current Drug Metabolism The Impact of Proteomics in the Understanding of the Molecular Basis of Paclitaxel-Resistance in Ovarian Tumors
Current Cancer Drug Targets Notch Inhibitors as a New Tool in the War on Cancer: A Pathway to Watch
Current Pharmaceutical Biotechnology