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Published on: February 6, 2015
Proteomics and Lipidomics Analysis Reveal That Membrane Remodeling and Extracellular Matrix Alterations Are Crucial
Shashwati Parihari1, Saheli Sarkar1, Vidhi Vashishtha1
1Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Abstract:
Cisplatin is a widely used chemotherapeutic agent for triple-negative breast cancer (TNBC), but resistance remains a major challenge. Understanding the molecular alterations driving this resistance is essential for identifying therapeutic targets. In this study, we employed an integrated proteomics and lipidomics approach to elucidate key pathways associated with cisplatin resistance. Employing high-resolution mass spectrometry, we conducted a comparative analysis between cisplatin-resistant (cisR) and cisplatin-sensitive (cisS) TNBC cell lines to discover resistance-associated alterations in protein and lipid expression. Proteomic analysis revealed overexpression of extracellular matrix (ECM) remodeling proteins, COL6A1, COL6A2, COL6A3, and VTN, that support epithelial-mesenchymal transition (EMT) and chemoresistance. Membrane-associated proteins such as TIMP2, MMP14, and APP were also elevated, indicating enhanced invasive and pro-survival signaling. Lipidomic alterations, including upregulation of FABP3, FABP4, LPL, and downregulation of PLA2G4A, indicated increased lipid uptake, metabolic rewiring, and membrane restructuring. Notably, elevated long-chain phosphatidylcholines and decreased sphingomyelins suggested increased membrane rigidity and reduced cisplatin permeability. Additionally, dysregulation of CDK activity through CCND2, CCND3, and CCNB2 overexpression indicated accelerated cell cycle progression and evasion of DNA damage checkpoints. Together, this integrative analysis highlights ECM remodeling, cytoskeletal dynamics, and lipid metabolism as major contributors to cisplatin resistance and identifies potential therapeutic markers for TNBC.
Insights
Cisplatin resistance in triple-negative breast cancer (TNBC) involves changes in extracellular matrix proteins, cell membrane lipids, and cell cycle regulation. Identifying these molecular alterations offers new therapeutic targets for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cisplatin is a key chemotherapy for triple-negative breast cancer (TNBC).
- Drug resistance significantly limits cisplatin's effectiveness in TNBC.
- Understanding resistance mechanisms is crucial for developing new therapies.
Purpose of the Study:
- To investigate the molecular basis of cisplatin resistance in TNBC.
- To identify key protein and lipid alterations associated with chemoresistance.
- To uncover potential therapeutic targets for overcoming cisplatin resistance.
Main Methods:
- Integrated proteomics and lipidomics analysis using high-resolution mass spectrometry.
- Comparative study of cisplatin-resistant (cisR) and cisplatin-sensitive (cisS) TNBC cell lines.
- Identification of differentially expressed proteins and lipids.
Main Results:
- Overexpression of extracellular matrix (ECM) remodeling proteins (COL6A1, COL6A2, COL6A3, VTN) linked to epithelial-mesenchymal transition (EMT) and chemoresistance.
- Elevated membrane-associated proteins (TIMP2, MMP14, APP) suggesting increased invasion and survival signaling.
- Lipidomic changes including upregulation of FABP3, FABP4, LPL and downregulation of PLA2G4A, indicating metabolic rewiring and membrane alterations.
- Increased long-chain phosphatidylcholines and decreased sphingomyelins suggesting reduced cisplatin permeability.
- Dysregulation of cell cycle regulators (CCND2, CCND3, CCNB2) indicating accelerated cell cycle progression and DNA damage evasion.
Conclusions:
- Cisplatin resistance in TNBC is associated with ECM remodeling, altered lipid metabolism, and accelerated cell cycle progression.
- Key proteins and lipids identified represent potential therapeutic targets.
- Integrated omics approaches are valuable for elucidating complex drug resistance mechanisms.
