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Integrin activation suppresses etoposide-induced DNA strand breakage in cultured murine tumor-derived endothelial
D G Hoyt1, J M Rusnak, R J Mannix
1Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Abstract:
Tumor endothelium is critical for solid tumor growth and is a potential site for anticancer drug action. Within 2 h, etoposide caused marked DNA strand breakage in xenograft tumor-derived endothelial cells (TDECs). Etoposide-induced DNA breakage was inhibited by culturing TDECs on gelatin, type IV collagen, laminin, fibronectin, and the integrin ligand hexapeptide, GRGDSP, but not the inactive peptide, GRADSP. It was also inhibited when TDECs were on surfaces coated with antibodies to alpha 5, beta 1, or beta 3 integrin subunits and by clustering integrins with soluble antibodies. After 8 h with etoposide, TDECs detached from the monolayer, and 50-kb DNA fragments were seen. Fibronectin inhibited both processes. Thus, integrins are survival factors for TDEC that inhibit the genotoxicity of etoposide and may influence the sensitivity of tumors to drugs.
Insights
Integrins on tumor endothelial cells protect them from etoposide-induced DNA damage. This suggests targeting integrins could enhance anticancer drug efficacy in solid tumors.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Tumor endothelium plays a vital role in solid tumor progression.
- It is a key target for anticancer therapies.
- Understanding endothelial cell responses to drugs is crucial.
Purpose of the Study:
- To investigate the role of integrins in the response of tumor-derived endothelial cells (TDECs) to etoposide.
- To determine if integrins modulate etoposide-induced genotoxicity and cell survival.
Main Methods:
- TDECs were cultured on various extracellular matrix proteins and peptides.
- Etoposide treatment was administered to TDECs.
- Inhibition of DNA strand breakage and cell detachment was assessed.
- Integrin function was modulated using antibodies and peptides.
Main Results:
- Etoposide induced significant DNA strand breakage in TDECs within 2 hours.
- This DNA damage was inhibited by extracellular matrix proteins (gelatin, collagen IV, laminin, fibronectin) and integrin-binding peptides (GRGDSP).
- Antibodies targeting α5, β1, and β3 integrin subunits, as well as integrin clustering, also inhibited etoposide-induced DNA breakage.
- After 8 hours, etoposide caused TDEC detachment and DNA fragmentation, effects inhibited by fibronectin.
Conclusions:
- Integrins function as survival factors for TDECs.
- Integrins inhibit the genotoxicity of etoposide in tumor endothelial cells.
- Modulating integrin activity may represent a strategy to enhance tumor sensitivity to chemotherapy.