Purchase this article with an account.
M. K. Krevosky, A. E. Galanis, J. A. Bowen, P. E. Kolovou, M. S. Gregory-Ksander, B. R. Ksander; Chemotherapy-Dependent Upregulation of Small Heat Shock Proteins in Retinoblastoma: Do They Mediate Chemoresistance?. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5340.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The small heat shock proteins (Hsps) αB-crystallin and Hsp27 inhibit apoptosis induced by diverse stimuli through inhibition of caspases. We previously demonstrated that αB-crystallin is expressed in 12 of 15 (80%) retinoblastoma (Rb) tumor samples, indicating αB-crystallin is frequently expressed in Rb. Since small Hsps confer resistance to chemotherapy in diverse cancers and since Rb tumors present with a wide range of sensitivity to chemotherapy, we hypothesize that expression of small Hsps will make Rb tumors more resistant to chemotherapy. We predict that Rb cells that lack Hsp expression will be more susceptible to treatment. Methods &
αB-crystallin was expressed in one of five primary Rb cell lines examined via immunocytochemistry and immunoblot analysis, while several express Hsp27. Two cell lines were chosen to further characterize the significance of αB-crystallin expression; Rb125 (αB-crystallin positive) and Rb143 (αB-crystallin negative). Morphological analysis revealed that the αB-crystallin negative Rb143 cells exhibit increased etoposide-induced apoptosis as compared to αB-crystallin positive Rb125 cells supporting a protective role for αB-crystallin in Rb. Preliminary immunoblot studies show a dose-dependent upregulation of Hsp27 following etoposide treatment in αB-crystallin negative Rb143 cells, but not in the αB-crystallin positive Rb125 cells, suggesting a potential redundancy of function for small Hsps. To further define the role of αB-crystallin in the sensitivity of these Rb cells to apoptosis, αB-crystallin will be downregulated in Rb125 via siRNA, while Rb143 will be transfected with αB-crystallin cDNA. These tumor cells will be selected and tested for their sensitivity to apoptosis, thereby providing a model to address whether αB-crystallin confers chemoresistance in Rb tumor cells.
αB-crystallin and Hsp27 may play critical roles in the chemoresistance of Rb due to inhibition of apoptosis. Defining the mechanisms of resistance will provide new therapeutic targets for clinically difficult cases. If linked to chemoresistance, αB-crystallin and Hsp27 can be downregulated in the tumor prior to treatment, increasing the sensitivity of the tumor to chemotherapy.
This PDF is available to Subscribers Only