Targeting HSP90/Survivin using a cell permeable structure based peptido-mimetic shepherdin in retinoblastoma

Nalini Venkatesan, Jagat R. Kanwar, Perinkulam Ravi Deepa, Saranya Navaneethakrishnan, Chitra Joseph, Subramanian Krishnakumar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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 (r2 = 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.

Original languageEnglish
Pages (from-to)141-149
Number of pages9
JournalChemico-Biological Interactions
Volume252
DOIs
Publication statusPublished - 25 May 2016
Externally publishedYes

Keywords

  • heat shock proteins
  • peptido-mimetic (shepherdin)
  • retinoblastoma
  • survivin

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