Abstract
Epidemiological evidence has linked the development and progression of several cancers including melanoma with obesity. However, whether obesity impinges on responses of cancer cells to treatment remains less understood. Here we report that human adipocytes contribute to resistance of melanoma cells to various therapeutic agents. Exposure to media from adipocyte cultures (adipocyte media) increased cell proliferation and reduced sensitivity of melanoma cells to apoptosis induced by diverse chemotherapeutic drugs, including the DNA-damaging drug cisplatin, the microtubuletargeting agent docetaxel, and the histone deacetylase inhibitor SAHA. This was associated with increased activation of PI3K/Akt and MEK/ERK signaling, and was attenuated by a PI3K or MEK inhibitor. The effect of adipocyte media on melanoma cells was, at least in part, due to the interaction between the adipokine leptin and its long form receptor OB-Rb, in that immunodepletion of leptin in adipocyte media or siRNA knockdown of OB-Rb in melanoma cells reversed the increase in Akt and ERK activation, enhancement in cell proliferation, and importantly, protection of melanoma cells against the drugs. In support, recombinant leptin partially recapitulated the effect of adipocyte media on melanoma cells. Of note, OB-Rb was increased on the surface of melanoma cells compared to melanocytes, whereas leptin short form receptors appeared to be suppressed post-transcriptionally, suggesting that OB-Rb was selectively upregulated in melanoma cells. Collectively, these results indicate that adipocytes contribute to the resistance of melanoma cells to chemotherapeutic drugs and agents targeting the PI3K/Akt and MEK/ERK pathways, and suggest that inhibition of the leptin/ OB-Rb system may be useful to improve the efficacy of multiple therapeutic approaches in the treatment of melanoma.
Keywords: Adipocyte, leptin, melanoma, obesity, PI3K/Akt, MEK/ERK.
Current Medicinal Chemistry
Title:Adipocytes Contribute to Resistance of Human Melanoma Cells to Chemotherapy and Targeted Therapy
Volume: 21 Issue: 10
Author(s): M. Chi, J. Chen, Y. Ye, Hsin-Yi Tseng, F. Lai, K.H. Tay, L. Jin, S.T. Guo, C.C. Jiang and X.D. Zhang
Affiliation:
Keywords: Adipocyte, leptin, melanoma, obesity, PI3K/Akt, MEK/ERK.
Abstract: Epidemiological evidence has linked the development and progression of several cancers including melanoma with obesity. However, whether obesity impinges on responses of cancer cells to treatment remains less understood. Here we report that human adipocytes contribute to resistance of melanoma cells to various therapeutic agents. Exposure to media from adipocyte cultures (adipocyte media) increased cell proliferation and reduced sensitivity of melanoma cells to apoptosis induced by diverse chemotherapeutic drugs, including the DNA-damaging drug cisplatin, the microtubuletargeting agent docetaxel, and the histone deacetylase inhibitor SAHA. This was associated with increased activation of PI3K/Akt and MEK/ERK signaling, and was attenuated by a PI3K or MEK inhibitor. The effect of adipocyte media on melanoma cells was, at least in part, due to the interaction between the adipokine leptin and its long form receptor OB-Rb, in that immunodepletion of leptin in adipocyte media or siRNA knockdown of OB-Rb in melanoma cells reversed the increase in Akt and ERK activation, enhancement in cell proliferation, and importantly, protection of melanoma cells against the drugs. In support, recombinant leptin partially recapitulated the effect of adipocyte media on melanoma cells. Of note, OB-Rb was increased on the surface of melanoma cells compared to melanocytes, whereas leptin short form receptors appeared to be suppressed post-transcriptionally, suggesting that OB-Rb was selectively upregulated in melanoma cells. Collectively, these results indicate that adipocytes contribute to the resistance of melanoma cells to chemotherapeutic drugs and agents targeting the PI3K/Akt and MEK/ERK pathways, and suggest that inhibition of the leptin/ OB-Rb system may be useful to improve the efficacy of multiple therapeutic approaches in the treatment of melanoma.
Export Options
About this article
Cite this article as:
Chi M., Chen J., Ye Y., Tseng Hsin-Yi, Lai F., Tay K.H., Jin L., Guo S.T., Jiang C.C. and Zhang X.D., Adipocytes Contribute to Resistance of Human Melanoma Cells to Chemotherapy and Targeted Therapy, Current Medicinal Chemistry 2014; 21 (10) . https://dx.doi.org/10.2174/0929867321666131129114742
DOI https://dx.doi.org/10.2174/0929867321666131129114742 |
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
-
Different Aspects of Head and Neck Squamous Cell Carcinoma: Cancer Stem Cells, their Niche and Targeted Therapy
Current Stem Cell Research & Therapy Small Molecule Complementarity As A Source of Novel Pharmaceutical Agents and Combination Therapies
Current Pharmaceutical Design Emerging Immunotargets and Immunotherapies in Prostate Cancer
Current Drug Targets Epigenetic Regulation of EMT: The Snail Story
Current Pharmaceutical Design Aminopeptidase N (APN/CD13) as a Target for Anti-Cancer Agent Design
Current Medicinal Chemistry AIDS Related Viruses, their Association with Leukemia, and Raf Signaling
Current HIV Research Synthetic Approach for Substituted 3-Amino-1,2,4-Triazines and their Chemical Reactivity and Biological Properties
Mini-Reviews in Organic Chemistry Effect of Flavonoids on Human Health: Old Subjects but New Challenges
Recent Patents on Biotechnology Development and Pharmacological Evaluation of a PEG Based Nanoparticulate Camptothecin Analog for Oral Administration
Current Drug Delivery The CXCL12/CXCR4 Axis as a Therapeutic Target in Cancer and HIV-1 Infection
Current Medicinal Chemistry Development of Novel Protein Scaffolds as Alternatives to Whole Antibodies for Imaging and Therapy: Status on Discovery Research and Clinical Validation
Current Pharmaceutical Biotechnology Structural and Functional Properties of Kunitz Proteinase Inhibitors from Leguminosae: A Mini Review
Current Protein & Peptide Science Newly Identified Tumor Antigens as Promising Cancer Vaccine Targets for Malignant Melanoma Treatment
Current Topics in Medicinal Chemistry In Silico Design of New B-Raf Kinase Type-II Inhibitors Through Combined Molecular Modeling Studies
Letters in Drug Design & Discovery Subject Index to Volume 3
Current Medicinal Chemistry - Anti-Cancer Agents Understanding Mouse Skin Carcinogenesis through Transgenic Approaches
Current Genomics Unfoldomics of Human Genetic Diseases: Illustrative Examples of Ordered and Intrinsically Disordered Members of the Human Diseasome
Protein & Peptide Letters APE1/Ref-1Role in Redox Signaling: Translational Applications of Targeting the Redox Function of the DNA Repair/Redox Protein APE1/Ref-1
Current Molecular Pharmacology Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches
Current Cancer Drug Targets Protective Effect of NSAIDs on Cancer and Influence of COX-2 C G Genotype
Current Cancer Drug Targets