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Published on: June 7, 2019
Comparative Proteomic Analysis of the Secretome of Control and BRAF/MEK Inhibitor-Resistant Melanoma Cells
Aleksandra Simiczyjew1, Magdalena Surman2, Magdalena Kot1
1Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland.
Abstract:
Treatment based on BRAF/MEK kinase inhibitors is one of the most commonly used methods in advanced melanoma therapy, but patients often develop resistance to treatment. Treatment-resistant cells can affect other cancer cells and the tumor microenvironment through the factors that they secrete. Therefore, this study aimed to examine the protein composition of the secretome of cells resistant to vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) and to compare it with that of nonresistant cells. Proteomic analysis, followed by gene ontology (GO) analysis, identified many differences in resistant melanoma cells' secretomes compared to controls (nonresistant). Many proteins upregulated in resistant melanoma cells compared to their nonresistant variants were directly related to cancer progression and associated with cell adhesion, actin cytoskeleton, matrix organization, proteolysis, and drug resistance. Proteins secreted by resistant melanoma cells can undoubtedly influence the surrounding microenvironment in a way that promotes the formation of a pro-tumor niche. Among the proteins secreted in significantly higher amounts by resistant cells (compared to the control group), which may be potential biomarkers or therapeutic targets in melanoma, plasminogen activator inhibitor 1, thymosin beta-4, clusterin, interleukin-6, superoxide dismutase, and selected matrix metalloproteinases can be distinguished.
Insights
Melanoma cells resistant to BRAF/MEK kinase inhibitors secrete proteins that promote tumor growth. Identifying these secreted proteins may lead to new melanoma treatments and biomarkers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Advanced melanoma treatment commonly uses BRAF/MEK kinase inhibitors.
- Acquired resistance to these inhibitors is a significant clinical challenge.
- Treatment-resistant cells influence the tumor microenvironment via secreted factors.
Purpose of the Study:
- To investigate the proteomic differences in the secretomes of vemurafenib/cobimetinib-resistant melanoma cells compared to nonresistant cells.
- To identify proteins secreted by resistant cells that may contribute to melanoma progression.
- To explore potential therapeutic targets and biomarkers for drug-resistant melanoma.
Main Methods:
- Proteomic analysis of melanoma cell secretomes.
- Comparison of protein expression between resistant and nonresistant cell lines.
- Gene Ontology (GO) analysis to interpret functional differences.
Main Results:
- Significant differences in protein composition were observed between resistant and nonresistant melanoma cell secretomes.
- Upregulated proteins in resistant cells are linked to cancer progression, including cell adhesion, matrix organization, and drug resistance.
- Specific proteins like plasminogen activator inhibitor 1, thymosin beta-4, clusterin, IL-6, SOD, and MMPs were found at higher levels in resistant cells.
Conclusions:
- Secreted proteins from resistant melanoma cells can create a pro-tumor microenvironment.
- These proteins represent potential biomarkers and therapeutic targets for overcoming BRAF/MEK inhibitor resistance in melanoma.
- Further research into these secreted factors is crucial for developing novel treatment strategies.
