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
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
-
Brain Tumor-Related Epilepsy
Current Neuropharmacology Editorial (Thematic Issue: Signal Transduction of Natural Products for Anticancer Therapy)
Current Signal Transduction Therapy Therapeutic Immunoconjugates. Which Cytotoxic Payload: Chemotherapeutic Drug (ADC) or Radionuclide (ARC) ?
Current Cancer Therapy Reviews Cartilage Oligomeric Matrix Protein: Matricellular and Matricrine Signaling in Cardiovascular Homeostasis and Disease
Current Vascular Pharmacology The Non-Canonical IκB Kinases IKKε and TBK1 as Potential Targets for the Development of Novel Therapeutic Drugs
Current Molecular Medicine Synthesis and Biological Activity of Chiral Dihydropyrazole: Potential Lead for Drug Design
Mini-Reviews in Medicinal Chemistry The Brain Endothelin System as Potential Target for Brain-Related Pathologies
Current Drug Targets - CNS & Neurological Disorders Stereotactic Body Radiotherapy in the Management of Head and Neck Malignancies
Current Cancer Therapy Reviews Radiation Induced Non-targeted Response: Mechanism and Potential Clinical Implications
Current Molecular Pharmacology CDC25A and B Dual-Specificity Phosphatase Inhibitors: Potential Agents for Cancer Therapy
Current Medicinal Chemistry Signalling Pathways Activated by Ultraviolet Radiation: Role in Ocular and Cutaneous Health
Current Pharmaceutical Design Induction of HT-29 Colon Cancer Cells Apoptosis by Pyrogallol with Growth Inhibiting Efficacy Against Drug-Resistant Helicobacter pylori
Anti-Cancer Agents in Medicinal Chemistry Topics of Physiological and Pathophysiological Functions of Lymphatics
Current Molecular Medicine Cytotoxic and Apoptotic Effects of Novel Pyrrolo[2,3-d]Pyrimidine Derivatives Containing Urea Moieties on Cancer Cell Lines
Anti-Cancer Agents in Medicinal Chemistry Sigma Receptors in Oncology: Therapeutic and Diagnostic Applications of Sigma Ligands
Current Pharmaceutical Design Evolution of Molecular Targets in Melanoma Treatment
Current Pharmaceutical Design The Ubiquitin-Proteasome System (UPS) and the Mechanism of Action of Bortezomib
Current Pharmaceutical Design CYP17 Inhibitors for Prostate Cancer Treatment – An Update
Current Medicinal Chemistry The State-of-Art in Angiogenic Properties of Latex from Different Plant Species
Current Angiogenesis (Discontinued) The Use of Fas Ligand, TRAIL and Bax in Gene Therapy of Prostate Cancer
Current Gene Therapy