Abstract
The mechanisms responsible for the switch of prostate cancer from androgen-sensitive (AS) to androgen-insensitive (AI) form are not well understood. Regulation of androgen receptor (AR), through which androgens control the expression of genes involved in prostate cells proliferation, migration and death also involves its cross-talk with the other signaling pathways, transcription factors and coregulatory proteins, such as β-catenin. With the aim to determine their possible contribution in triggering the switch from AS to AI form, which occurs upon androgen deprivation therapy - AR, Akt and β-catenin expression were knocked-down with respective siRNAs. Treatment of LNCaP prostate cells with siRNA for AR significantly reduced their proliferation (45-70%), expression of nuclear β- catenin, cyclin-D1, cyclin-G1, c-Myc as well as activity of metalloproteinases (MMPs) -2,-7,-9 and cell migration. Surprisingly, after longer (over 72 hrs) silencing of AR in LNCaP cells, elevated levels of p-Akt were detected and enhanced proliferation as well as expression of nuclear β-catenin, cyclin-D1, c-Myc and activity of MMPs were observed. Such effects were not observed in either PC-3 or DU145 AI cells. However, silencing of Akt and /or β-catenin in those as well as in LNCaP cells led to their decreased proliferation and migration. Our findings suggest that in prostate cancer cells, either AR or Akt signaling prevails, depending on their initial androgen sensitivity and its availability. In AI prostate cancer cells, Akt takes over the role of AR and more effectively contributes through the same signaling molecule, β-catenin, to AI cancer progression.
Keywords: Akt, androgen-insensitive, androgen-sensitive, androgen receptor, β-catenin, metalloproteinases, prostate cancer, cyclin-D1, c-Myc, siRNA
Current Medicinal Chemistry
Title:Increased Akt Signaling Resulting from the Loss of Androgen Responsiveness in Prostate Cancer
Volume: 20 Issue: 1
Author(s): J. Dulinska-Litewka, J.A. McCubrey and P. Laidler
Affiliation:
Keywords: Akt, androgen-insensitive, androgen-sensitive, androgen receptor, β-catenin, metalloproteinases, prostate cancer, cyclin-D1, c-Myc, siRNA
Abstract: The mechanisms responsible for the switch of prostate cancer from androgen-sensitive (AS) to androgen-insensitive (AI) form are not well understood. Regulation of androgen receptor (AR), through which androgens control the expression of genes involved in prostate cells proliferation, migration and death also involves its cross-talk with the other signaling pathways, transcription factors and coregulatory proteins, such as β-catenin. With the aim to determine their possible contribution in triggering the switch from AS to AI form, which occurs upon androgen deprivation therapy - AR, Akt and β-catenin expression were knocked-down with respective siRNAs. Treatment of LNCaP prostate cells with siRNA for AR significantly reduced their proliferation (45-70%), expression of nuclear β- catenin, cyclin-D1, cyclin-G1, c-Myc as well as activity of metalloproteinases (MMPs) -2,-7,-9 and cell migration. Surprisingly, after longer (over 72 hrs) silencing of AR in LNCaP cells, elevated levels of p-Akt were detected and enhanced proliferation as well as expression of nuclear β-catenin, cyclin-D1, c-Myc and activity of MMPs were observed. Such effects were not observed in either PC-3 or DU145 AI cells. However, silencing of Akt and /or β-catenin in those as well as in LNCaP cells led to their decreased proliferation and migration. Our findings suggest that in prostate cancer cells, either AR or Akt signaling prevails, depending on their initial androgen sensitivity and its availability. In AI prostate cancer cells, Akt takes over the role of AR and more effectively contributes through the same signaling molecule, β-catenin, to AI cancer progression.
Export Options
About this article
Cite this article as:
Dulinska-Litewka J., McCubrey J.A. and Laidler P., Increased Akt Signaling Resulting from the Loss of Androgen Responsiveness in Prostate Cancer, Current Medicinal Chemistry 2013; 20 (1) . https://dx.doi.org/10.2174/0929867311302010014
DOI https://dx.doi.org/10.2174/0929867311302010014 |
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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Recent Nanocarrier Approaches for Targeted Drug Delivery in Cancer Therapy
Current Molecular Pharmacology Pregnancy and Postpartum Influences on Rheumatoid Arthritis Activity:Natures Model to Investigate Systemic Biological Mechanisms in the Disease
Current Rheumatology Reviews Metals and Metal Derivatives in Medicine
Mini-Reviews in Medicinal Chemistry Metabolic Response Assessment in Non-Small Cell Lung Cancer Patients after Platinum-Based Therapy: A Preliminary Analysis
Current Medical Imaging Editorial [Hot Topic: Targeted Alpha Therapy – Part II (Guest Editor: Jorgen Elgqvist)]
Current Radiopharmaceuticals MicroRNA-183 Functions As an Oncogene by Regulating PDCD4 in Gastric Cancer
Anti-Cancer Agents in Medicinal Chemistry Biological Abilities of Rice Bran-Derived Antioxidant Phytochemicals for Medical Therapy
Current Topics in Medicinal Chemistry ABC Transporters as Potential Targets for Modulation of Drug Resistance
Mini-Reviews in Medicinal Chemistry Impact of Epigenetic Dietary Components on Cancer through Histone Modifications
Current Medicinal Chemistry Advanced Neoplastic Disease as Immunologic, Endocrine and Metabolic Disorder
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry The Role of Melatonin in the Immuno-Neuro-Psychology of Mental Disorders
Recent Patents on CNS Drug Discovery (Discontinued) PNP Anticancer Gene Therapy
Current Topics in Medicinal Chemistry Expression of Heme Oxygenase-1 in Response to Proteasomal Inhibition
Protein & Peptide Letters Melatonin: Pharmacology, Functions and Therapeutic Benefits
Current Neuropharmacology Affinity-Based Methods in Drug-Target Discovery
Current Drug Targets From Nucleic Acids to Drug Discovery: Nucleobases as Emerging Templates for Drug Candidates
Current Medicinal Chemistry Light Directed Gene Transfer by Photochemical Internalisation
Current Gene Therapy Characterization of β-Sitosterol for Potential Selective GR Modulation
Protein & Peptide Letters Role of PARP Inhibitors in Cancer Biology and Therapy
Current Medicinal Chemistry Pluronic-Based Core/Shell Nanoparticles for Drug Delivery and Diagnosis
Current Medicinal Chemistry