Abstract
Expression levels of intact tumor suppressor proteins and molecular targets of anti-neoplastic agents are critical in defining cancer cell drug sensitivity; however, the intracellular location of a specific protein may be as important. Many tumor suppressor proteins must be present in the cell nucleus to perform their policing activities or for the cell to respond to chemotherapeutic agents. Nuclear proteins needed to prevent cancer initiation or progression or to optimize chemotherapeutic response include the tumor suppressor proteins p53, APC/β-catenin, and FOXO family genes; negative regulators of cell cycle progression and survival such as p21CIP1and p27KIP1; and chemotherapeutic targets such as DNA topoisomerases I and IIα. Mislocalization of a nuclear protein into the cytoplasm can render it ineffective as a tumor suppressor or as a target for chemotherapy. Blocking nuclear export of any or all of these proteins may restore tumor suppression or apoptosis or, for topoisomerases I and IIα, reverse drug resistance to inhibitors of these enzymes. During disease progression or in response to the tumor environment, cancer cells appear to acquire intracellular mechanisms to export anti-cancer nuclear proteins. These mechanisms generally involve modification of nuclear proteins, causing the proteins to reveal leucine-rich nuclear export signal protein sequences. Subsequent export is mediated by CRM1. This review defines the general processes involved in nuclear export mediated by CRM1/RanGTP (exportin/XPO1), examines the functions of individual tumor suppressor nuclear proteins and nuclear targets of chemotherapy, and explores potential mechanisms of cancer cells to induce export of these proteins. Novel drugs that could potentially counteract nuclear export of specific proteins are also discussed.
Keywords: CRM1, drug resistance, topoisomerase I, topoisomerase IIα, p53, APC/β-catenin, FOXO, P21cip1, p27KIP1
Current Medicinal Chemistry
Title: CRM1-Mediated Nuclear Export of Proteins and Drug Resistance in Cancer
Volume: 15 Issue: 26
Author(s): Joel G. Turner and Daniel M. Sullivan
Affiliation:
Keywords: CRM1, drug resistance, topoisomerase I, topoisomerase IIα, p53, APC/β-catenin, FOXO, P21cip1, p27KIP1
Abstract: Expression levels of intact tumor suppressor proteins and molecular targets of anti-neoplastic agents are critical in defining cancer cell drug sensitivity; however, the intracellular location of a specific protein may be as important. Many tumor suppressor proteins must be present in the cell nucleus to perform their policing activities or for the cell to respond to chemotherapeutic agents. Nuclear proteins needed to prevent cancer initiation or progression or to optimize chemotherapeutic response include the tumor suppressor proteins p53, APC/β-catenin, and FOXO family genes; negative regulators of cell cycle progression and survival such as p21CIP1and p27KIP1; and chemotherapeutic targets such as DNA topoisomerases I and IIα. Mislocalization of a nuclear protein into the cytoplasm can render it ineffective as a tumor suppressor or as a target for chemotherapy. Blocking nuclear export of any or all of these proteins may restore tumor suppression or apoptosis or, for topoisomerases I and IIα, reverse drug resistance to inhibitors of these enzymes. During disease progression or in response to the tumor environment, cancer cells appear to acquire intracellular mechanisms to export anti-cancer nuclear proteins. These mechanisms generally involve modification of nuclear proteins, causing the proteins to reveal leucine-rich nuclear export signal protein sequences. Subsequent export is mediated by CRM1. This review defines the general processes involved in nuclear export mediated by CRM1/RanGTP (exportin/XPO1), examines the functions of individual tumor suppressor nuclear proteins and nuclear targets of chemotherapy, and explores potential mechanisms of cancer cells to induce export of these proteins. Novel drugs that could potentially counteract nuclear export of specific proteins are also discussed.
Export Options
About this article
Cite this article as:
Turner G. Joel and Sullivan M. Daniel, CRM1-Mediated Nuclear Export of Proteins and Drug Resistance in Cancer, Current Medicinal Chemistry 2008; 15 (26) . https://dx.doi.org/10.2174/092986708786242859
DOI https://dx.doi.org/10.2174/092986708786242859 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
- Announcements
Related Articles
-
Therapeutic Application of Histone Deacetylase Inhibitors for Stroke
Central Nervous System Agents in Medicinal Chemistry Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer
Current Vascular Pharmacology Manipulation of Dendritic Cells for Tumor Immunity
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Role of Chemokines and Their Receptors in Cancer
Current Pharmaceutical Design Malaria and artemisinin derivatives: an updated review
Mini-Reviews in Medicinal Chemistry SCF E3 Ubiquitin Ligases as Anticancer Targets
Current Cancer Drug Targets The DREAM of Pain Relief
Current Rheumatology Reviews Antioxidant Properties of Crocus Sativus L. and Its Constituents and Relevance to Neurodegenerative Diseases; Focus on Alzheimer’s and Parkinson’s Disease
Current Neuropharmacology Scope of Lipid Nanoparticles in Neuroscience: Impact on the Treatment of Neurodegenerative Diseases
Current Pharmaceutical Design Melatonin, its Metabolites and its Synthetic Analogs as Multi-Faceted Compounds: Antioxidant, Prooxidant and Inhibitor of Bioactivation Reactions
Current Medicinal Chemistry Novel Pharmacodynamic Approach to Assess Obatoclax (GX15-070) and Bortezomib (BTZ) Synergism in Non-Hodgkin’s Lymphoma
Clinical Cancer Drugs Natural Compounds as Antagonists of Canonical Wnt/β-Catenin Signaling
Current Chemical Biology Novel Agents Aiming at Specific Molecular Targets Increase Chemosensitivity and Overcome Chemoresistance in Hematopoietic Malignancies
Current Pharmaceutical Design Tubulins as Therapeutic Targets in Cancer: from Bench to Bedside
Current Pharmaceutical Design The Endocannabinoid System in the Cancer Therapy: An Overview
Current Medicinal Chemistry Gastrin-Releasing Peptide Receptors Regulate Proliferation of C6 Glioma Cells through a Phosphatidylinositol 3-Kinase-Dependent Mechanism
Current Neurovascular Research Hypoxia Selects for a Quiescent, CML Stem/Leukemia Initiating- Like Population Dependent on CBP/Catenin Transcription
Current Molecular Pharmacology Conformational Diseases and Structure-Toxicity Relationships: Lessons from Prion-Derived Peptides
Current Protein & Peptide Science Interactions of Curcumin and Its Derivatives with Nucleic Acids and their Implications
Mini-Reviews in Medicinal Chemistry Metallothionein as a Scavenger of Free Radicals - New Cardioprotective Therapeutic Agent or Initiator of Tumor Chemoresistance?
Current Drug Targets