TY - JOUR
T1 - Targeting HSP90/Survivin using a cell permeable structure based peptido-mimetic shepherdin in retinoblastoma
AU - Venkatesan, Nalini
AU - Kanwar, Jagat R.
AU - Deepa, Perinkulam Ravi
AU - Navaneethakrishnan, Saranya
AU - Joseph, Chitra
AU - Krishnakumar, Subramanian
PY - 2016/5/25
Y1 - 2016/5/25
N2 - 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.
AB - 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.
KW - heat shock proteins
KW - peptido-mimetic (shepherdin)
KW - retinoblastoma
KW - survivin
UR - http://www.scopus.com/inward/record.url?scp=84964528228&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2016.04.011
DO - 10.1016/j.cbi.2016.04.011
M3 - Article
C2 - 27062892
AN - SCOPUS:84964528228
VL - 252
SP - 141
EP - 149
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
SN - 0009-2797
ER -