title: Endoglin (CD105) contributes to platinum resistance and is a target for tumor-specific therapy in epithelial ovarian cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Departments of Obstetrics and Gynecology, Radiation Oncology, and Pathology, University of Alabama at Birmingham, Birmingham, AL 35249, USA.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Ziebarth
authors.forename: Somaira
authors.initials: S
authors.lastname: Nowsheen
authors.forename: Adam D
authors.initials: AD
authors.lastname: Steg
authors.forename: Monjri M
authors.initials: MM
authors.lastname: Shah
authors.forename: Ashwini A
authors.initials: AA
authors.lastname: Katre
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Dobbin
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Michael
authors.initials: M
authors.lastname: Conner
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000071063:Endoglin; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D010984:Platinum / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D010984:Platinum