Adipocytes contribute to resistance of human melanoma cells to chemotherapy and targeted therapy.

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.

• Authors: M Chi, J Chen, Y Ye, Hsin-Yi Tseng, F Lai, K H Tay, L Jin, S T Guo, C C Jiang, X D Zhang
• Journal: Current medicinal chemistry (Curr Med Chem) Vol. 21 Issue 10 Pg. 1255-67 (Apr 2014) ISSN: 1875-533X [Electronic] United Arab Emirates
• PMID: 24304284 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Culture Media, Conditioned
• Histone Deacetylase Inhibitors
• Leptin
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Receptors, Leptin
• Taxoids
• Docetaxel
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase Kinases
• Cisplatin

Topics

• Adipocytes (cytology, metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Culture Media, Conditioned (pharmacology)
• Docetaxel
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Keratinocytes (drug effects, metabolism, pathology)
• Leptin (deficiency, genetics)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, genetics, metabolism)
• Molecular Targeted Therapy
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Receptors, Leptin (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Taxoids (pharmacology)