Abstract
Focal Adhesion Kinase is a 125 kDa non-receptor kinase and overexpressed in many types of tumors. Recently, short noncoding RNAs, called microRNAs have been discovered as regulators of gene expression mainly through binding to the untranslated region (UTR) of mRNA. In this report we show that MiR-138 and MiR-135 down-regulated FAK expression in cancer cells. MiR-138 and MiR-135 inhibited FAK protein expression in different cancer cell lines. The computer analysis of 3’FAK-untranslated region (FAKUTR) identified one conserved MiR-138 binding site (CACCAGCA) at positions 3514-3521 and one conserved MiR-135 (AAGCCAU) binding site at positions 4278-4284 in the FAK-UTR. By a dual-luciferase assay we demonstrate that MiR-138 and MiR-135 directly bound the FAK untranslated region using FAK-UTR-Target (FAK-UTR) luciferase plasmid and inhibited its luciferase activity. The sitedirected mutagenesis of the MiR-138 and MiR-135 binding sites in the FAK-UTR abrogated MiR-138 and MiR-135-directed inhibition of FAK-UTR. Real-time PCR demonstrated that cells transfected with MiR-138 and MiR-135 expressed decreased FAK mRNA levels. Moreover, stable expression of MiR-138 and MiR-135 in 293 and HeLa cells decreased cell invasion and increased sensitivity to 5- fluorouracil (5-FU), FAK inhibitor, Y15, and doxorubicin. In addition, MiR-138 significantly decreased 293 xenograft tumor growth in vivo. This is the first report on regulation of FAK expression by MiR-135 and MiR138 that affected invasion, drug sensitivity, and tumor growth in cancer cells, which is important to the development of FAK-targeted therapeutics and understanding their novel regulations and functions.
Keywords: Cancer, expression, Focal Adhesion Kinase, invasion, microRNA, tumor.
Anti-Cancer Agents in Medicinal Chemistry
Title:MiR-138 and MiR-135 Directly Target Focal Adhesion Kinase, Inhibit Cell Invasion, and Increase Sensitivity to Chemotherapy in Cancer Cells
Volume: 14 Issue: 1
Author(s): Vita M. Golubovskaya, Brittany Sumbler, Baotran Ho, Michael Yemma and William G. Cance
Affiliation:
Keywords: Cancer, expression, Focal Adhesion Kinase, invasion, microRNA, tumor.
Abstract: Focal Adhesion Kinase is a 125 kDa non-receptor kinase and overexpressed in many types of tumors. Recently, short noncoding RNAs, called microRNAs have been discovered as regulators of gene expression mainly through binding to the untranslated region (UTR) of mRNA. In this report we show that MiR-138 and MiR-135 down-regulated FAK expression in cancer cells. MiR-138 and MiR-135 inhibited FAK protein expression in different cancer cell lines. The computer analysis of 3’FAK-untranslated region (FAKUTR) identified one conserved MiR-138 binding site (CACCAGCA) at positions 3514-3521 and one conserved MiR-135 (AAGCCAU) binding site at positions 4278-4284 in the FAK-UTR. By a dual-luciferase assay we demonstrate that MiR-138 and MiR-135 directly bound the FAK untranslated region using FAK-UTR-Target (FAK-UTR) luciferase plasmid and inhibited its luciferase activity. The sitedirected mutagenesis of the MiR-138 and MiR-135 binding sites in the FAK-UTR abrogated MiR-138 and MiR-135-directed inhibition of FAK-UTR. Real-time PCR demonstrated that cells transfected with MiR-138 and MiR-135 expressed decreased FAK mRNA levels. Moreover, stable expression of MiR-138 and MiR-135 in 293 and HeLa cells decreased cell invasion and increased sensitivity to 5- fluorouracil (5-FU), FAK inhibitor, Y15, and doxorubicin. In addition, MiR-138 significantly decreased 293 xenograft tumor growth in vivo. This is the first report on regulation of FAK expression by MiR-135 and MiR138 that affected invasion, drug sensitivity, and tumor growth in cancer cells, which is important to the development of FAK-targeted therapeutics and understanding their novel regulations and functions.
Export Options
About this article
Cite this article as:
Golubovskaya M. Vita, Sumbler Brittany, Ho Baotran, Yemma Michael and Cance G. William, MiR-138 and MiR-135 Directly Target Focal Adhesion Kinase, Inhibit Cell Invasion, and Increase Sensitivity to Chemotherapy in Cancer Cells, Anti-Cancer Agents in Medicinal Chemistry 2014; 14 (1) . https://dx.doi.org/10.2174/187152061401140108113435
DOI https://dx.doi.org/10.2174/187152061401140108113435 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
-
Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations
Current Pharmaceutical Design Peptides for Therapy and Diagnosis of Alzheimer's Disease
Current Pharmaceutical Design Anticancer Evaluation of 3,4,5,4'-trans-tetramethoxystilbene (DMU-212) and Its Analogs Against an Extensive Panel of Human Tumor Cell Lines
Letters in Drug Design & Discovery Biological Responses to Hydrogen Molecule and its Preventive Effects on Inflammatory Diseases
Current Pharmaceutical Design PROTACs: Promising Approaches for Epigenetic Strategies to Overcome Drug Resistance
Current Cancer Drug Targets Detection of Tumor Markers with ProteinChip® Technology
Current Pharmaceutical Biotechnology Inhibition of Early Biochemical Defects in Prodromal Huntington’s disease by Simultaneous Activation of Nrf2 and Elevation of Multiple Micronutrients
Current Aging Science Molecular Classification and Drug Response Prediction in Cancer
Current Drug Targets Essential Oils as Active Ingredients of Lipid Nanocarriers for Chemotherapeutic Use
Current Pharmaceutical Biotechnology Mast Cells as Targets of Pimecrolimus
Current Pharmaceutical Design Characterization of LC-HCC Fusion Protein of Botulinum Neurotoxin Type A
Protein & Peptide Letters From Multiple PAR1 Receptor/Protein Interactions to their Multiple Therapeutic Implications
Current Topics in Medicinal Chemistry Genetic Engineering of AAV Capsid Gene for Gene Therapy Application
Current Gene Therapy MYC as Therapeutic Target for Embryonal Tumors: Potential and Challenges
Current Cancer Drug Targets Novobiocin and Additional Inhibitors of the Hsp90 C-Terminal Nucleotide- binding Pocket
Current Medicinal Chemistry Endocannabinoids and Their Receptors: Physiology, Pathology and Pharmacology
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Cellular Immunotherapy for Neuroblastoma: A Review of Current Vaccine and Adoptive T Cell Therapeutics
Current Pharmaceutical Design Involvement of Cannabinoids in Cellular Proliferation
Mini-Reviews in Medicinal Chemistry Small Diverse Antioxidant Functionalities for Oxidative Stress Disease Drug Discovery
Mini-Reviews in Medicinal Chemistry Cloning and Transcriptional Regulation of Genes Responsible for Synthesis of Gangliosides
Current Drug Targets