RRC ID 51693
Author Venkatesan N, Kanwar JR, Deepa PR, Navaneethakrishnan S, Joseph C, Krishnakumar S.
Title Targeting HSP90/Survivin using a cell permeable structure based peptido-mimetic shepherdin in retinoblastoma.
Journal Chem. Biol. Interact.
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.
CONCLUSION: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.
Volume 252
Pages 141-9
Published 2016-5-25
DOI 10.1016/j.cbi.2016.04.011
PII S0009-2797(16)30134-X
PMID 27062892
MeSH Antineoplastic Agents / pharmacology* Apoptosis / drug effects Cell Line, Tumor Cell Survival / drug effects HSP70 Heat-Shock Proteins / metabolism HSP90 Heat-Shock Proteins / metabolism* Humans Matrix Metalloproteinase 2 / metabolism Peptide Fragments / pharmacology* Retina / drug effects* Retina / metabolism Retina / pathology Retinal Neoplasms / drug therapy* Retinal Neoplasms / metabolism Retinal Neoplasms / pathology Retinoblastoma / drug therapy* Retinoblastoma / metabolism Retinoblastoma / pathology
IF 3.296
Human and Animal Cells Y79(RCB1645)