title: Targeting HSP90/Survivin using a cell permeable structure based peptido-mimetic shepherdin in retinoblastoma.
abstract: BACKGROUND
  Retinoblastoma (RB) is a childhood retinal malignancy. Effective therapeutic strategies are still being investigated in RB disease management. Here, the anti-cancer effect of shepherdin, a peptido-mimetic inhibiting heat shock protein (HSP90)-Survivin interaction has been analyzed.
  
  
  METHODS
  We analyzed HSP (HSP70/90) and Survivin protein expressions by immunohistochemistry (29 archival tumors), qRT-PCR, FACS and Western analysis (10 un-fixed RB tumors). We also analyzed cellular cytotoxicity and anti-proliferative effect in peptide treated RB cells (Y79, Weri Rb1) and MIO-M1 cells.
  
  
  RESULTS
  Heterogeneous expressions of HSP70/90 and Survivin with a significant association between HSP70 and HSP90 (r(2) = 0.59, p = 0.001) was observed. In RB cells, anti-tumor effects were detected with 0.42 μg/ml of shepherdin at 4 h s of serum starvation. Decreased Survivin, Bcl2, MMP-2 activity with increased Bax, Bim, and Caspase-9 protein expressions were noticed. No significant changes were observed in shepherdin treated non-neoplastic MIO-M1, nor in scramble-peptide treated RB cells.
  
  
  CONCLUSIONS
  The presence of HSPs (HSP70/90) and Survivin reveals multiple cellular mechanisms adopted by RB cells during cancer progression. Serum starvation induced HSP90 whose interactions with Survivin were specifically inhibited by shepherdin. The associated molecular shuffling has been reported. These findings strongly implicate the potential of targeting HSP90-Survivin interaction as an adjuvant therapy in RB management.
authors.affiliation: Department of Larsen & Toubro Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College Road, Chennai 600006, India; Birla Institute of Technology and Science (BITS), Pilani, Rajasthan 333031, India.
authors.forename: Nalini
authors.initials: N
authors.lastname: Venkatesan
authors.affiliation: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR) Strategic Research Centre, Faculty of Health, Deakin University, Pigdons Road, Waurn Ponds, Geelong, Victoria 3217, Australia.
authors.forename: Jagat R
authors.initials: JR
authors.lastname: Kanwar
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science (BITS), Pilani, Rajasthan 333031, India.
authors.forename: Perinkulam Ravi
authors.initials: PR
authors.lastname: Deepa
authors.affiliation: Department of Larsen & Toubro Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College Road, Chennai 600006, India.
authors.forename: Saranya
authors.initials: S
authors.lastname: Navaneethakrishnan
authors.affiliation: Department of Larsen & Toubro Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College Road, Chennai 600006, India.
authors.forename: Chitra
authors.initials: C
authors.lastname: Joseph
authors.affiliation: Department of Larsen & Toubro Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College Road, Chennai 600006, India. Electronic address: drkrishnakumar_2000@yahoo.com.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnakumar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D010446:Peptide Fragments; C503112:shepherdin; D020778:Matrix Metalloproteinase 2
keywords: Heat shock proteins; Peptido-mimetic (shepherdin); Retinoblastoma; Survivin