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Endoglin (CD105) contributes to platinum resistance and is a target for tumor-specific therapy in epithelial ovarian cancer
- Publication Year :
- 2012
-
Abstract
- Purpose: Endoglin (CD105) is a membranous protein overexpressed in tumor-associated endothelial cells, chemoresistant populations of ovarian cancer cells, and potentially stem cells. Our objective was to evaluate the effects and mechanisms of targeting endoglin in ovarian cancer. Experimental Design: Global and membranous endoglin expression was evaluated in multiple ovarian cancer lines. In vitro, the effects of siRNA-mediated endoglin knockdown with and without chemotherapy were evaluated by MTT assay, cell-cycle analysis, alkaline comet assay, γ-H2AX foci formation, and quantitative PCR. In an orthotopic mouse model, endoglin was targeted with chitosan-encapsulated siRNA with and without carboplatin. Results: Endoglin expression was surprisingly predominantly cytoplasmic, with a small population of surface-positive cells. Endoglin inhibition decreased cell viability, increased apoptosis, induced double-stranded DNA damage, and increased cisplatin sensitivity. Targeting endoglin downregulates expression of numerous DNA repair genes, including BARD1, H2AFX, NBN, NTHL1, and SIRT1. BARD1 was also associated with platinum resistance, and was induced by platinum exposure. In vivo, antiendoglin treatment decreased tumor weight in both ES2 and HeyA8MDR models when compared with control (35%–41% reduction, P < 0.05). Endoglin inhibition with carboplatin was associated with even greater inhibitory effect when compared with control (58%–62% reduction, P < 0.001). Conclusions: Endoglin downregulation promotes apoptosis, induces significant DNA damage through modulation of numerous DNA repair genes, and improves platinum sensitivity both in vivo and in vitro. Antiendoglin therapy would allow dual treatment of both tumor angiogenesis and a subset of aggressive tumor cells expressing endoglin and is being actively pursued as therapy in ovarian cancer. Clin Cancer Res; 19(1); 170–82. ©2012 AACR.
- Subjects :
- Cancer Research
DNA Repair
DNA repair
DNA damage
Cell Survival
Population
Mice, Nude
Antineoplastic Agents
Receptors, Cell Surface
Biology
Carcinoma, Ovarian Epithelial
Article
chemistry.chemical_compound
Mice
Antigens, CD
hemic and lymphatic diseases
otorhinolaryngologic diseases
medicine
Animals
Humans
Viability assay
Neoplasms, Glandular and Epithelial
education
Platinum
Ovarian Neoplasms
education.field_of_study
Endoglin
Cancer
medicine.disease
Carboplatin
Gene Expression Regulation, Neoplastic
Disease Models, Animal
Oncology
chemistry
Drug Resistance, Neoplasm
Cancer research
Female
RNA Interference
Ovarian cancer
DNA Damage
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....4549fad5ffada486bf269e6c16dc29b4