title: Therapeutic targeting of PELP1 prevents ovarian cancer growth and metastasis.
abstract: OBJECTIVE
  Ovarian cancer remains a major threat to women's health, partly due to difficulty in early diagnosis and development of metastases. A critical need exists to identify novel targets that curb the progression and metastasis of ovarian cancer. In this study, we examined whether the nuclear receptor coregulator PELP1 (proline-, glutamic acid-, leucine-rich protein-1) contributes to progression and metastatic potential of ovarian cancer cells and determined whether blocking of the PELP1 signaling axis had a therapeutic effect.
  
  
  METHODS
  Ovarian cancer cells stably expressing PELP1-shRNA (short hairpin RNA) were established. Fluorescent microscopy, Boyden chamber, invasion assays, wound healing, and zymography assays were performed to examine the role of PELP1 in metastasis. Expression analysis of the model cells was conducted using tumor metastasis microarray to identify PELP1 Target genes. Therapeutic potential of PELP1-siRNA in vivo was determined using a nanoliposomal formulation of PELP1-siRNA-DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) administered systemically in a xenograft model.
  
  
  RESULTS
  PELP1 knockdown caused cytoskeletal defects and significantly affected the migratory potential of ovarian cancer cells. Microarray analysis revealed that PELP1 affected the expression of selective genes involved in metastasis including Myc, MTA1, MMP2, and MMP9. Zymography analysis confirmed that PELP1 knockdown caused a decrease in the activation of matrix metalloproteases (MMP) 2 and MMP9. Compared with control siRNA-DOPC-treated mice, animals injected with PELP1-siRNA-DOPC had 54% fewer metastatic tumor nodules, exhibited a 51% reduction in tumor growth and an 84% reduction in ascites volume.
  
  
  CONCLUSIONS
  The results suggest that PELP1 signaling axis is a potential druggable target and liposomal PELP1-siRNA-DOPC could be used as a novel drug to prevent or treat ovarian metastasis.
authors.affiliation: Department of Obstetrics and Gynecology, CTRC, The UT Health Science Center, San Antonio, Texas 78229, USA.
authors.forename: Dimple
authors.initials: D
authors.lastname: Chakravarty
authors.forename: Sudipa Saha
authors.initials: SS
authors.lastname: Roy
authors.forename: Challa Ram
authors.initials: CR
authors.lastname: Babu
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Dandamudi
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.forename: Pablo
authors.initials: P
authors.lastname: Vivas-Mejia
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056970:Co-Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D010713:Phosphatidylcholines / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D056970:Co-Repressor Proteins; D008081:Liposomes; C438485:PELP1 protein, human; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D014157:Transcription Factors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C017251:1,2-oleoylphosphatidylcholine