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

• Published in: Chemico-biological interactions 2016-05, Vol.252, p.141-149
• Main Authors: Venkatesan, Nalini, Kanwar, Jagat R., Deepa, Perinkulam Ravi, Navaneethakrishnan, Saranya, Joseph, Chitra, Krishnakumar, Subramanian
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Heat shock proteins; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - metabolism; Humans; Matrix Metalloproteinase 2 - metabolism; Peptide Fragments - pharmacology; Peptido-mimetic (shepherdin); Retina - drug effects; Retina - metabolism; Retina - pathology; Retinal Neoplasms - drug therapy; Retinal Neoplasms - metabolism; Retinal Neoplasms - pathology; Retinoblastoma; Retinoblastoma - drug therapy; Retinoblastoma - metabolism; Retinoblastoma - pathology; Survivin
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2016.04.011

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. 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. 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. 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. •HSP70/90 and Survivin expressions in primary Retinoblastoma tissues are reported.•Treatment of shepherdin, targeting HSP90/Survivin has anti-cancer effect in RB.•Shepherdin treatment causes molecular shuffling (Bax, Bim, Bcl2, caspase-9, MMPs).•Negligible toxicity in normal cells treated with shepherdin.•Targeting HSP90/Survivin may be a promising adjuvant therapy for RB implicated.