Role of Survivin and Small Heat Shock Proteins in the Chemoresistance of Retinoblastoma

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Retinoblastoma (Rb) is a rare ocular malignancy affecting 1 in 20,000 pediatric patients. Current treatment regimens employ the use of chemotherapy prior to additional treatment modalities to reduce tumor size, often via apoptosis. However, proteins that inhibit apoptosis are commonly expressed in diverse cancers, conferring cellular survival and resistance to death. One mechanism by which apoptosis is prevented is through increased expression of cellular survival proteins, including inhibitors of apoptosis (IAPs) and heat shock proteins (Hsps). Since Rb tumors present with a wide range of sensitivity to chemotherapy, the hypothesis to be addressed is that expression of IAPs and small Hsps make Rb tumors more resistant to chemotherapy. To define expression of IAPs and Hsps in Rb cells, three proteins that ultimately prevent apoptosis through inhibition of Caspase-3 activation were analyzed. One important IAP is Survivin which is selectively expressed in cancer cells and absent in healthy cells. Survivin's selective expression may explain the chemoresistant nature of cancerous cells and as such, has great therapeutic potential. Moreover, previous studies of diverse tumor types demonstrate a correlation between the upregulation of the small Hsps, βB-crystallin and Hsp27, and poor prognosis in patients. Through Western blot analysis and immunocytochemistry, Survivin and Hsp27 expression was observed in four of five primary human Rb cell lines examined, while αB-crystallin was expressed in only one of five Rb cell lines analyzed. In order to address a clinically relevant therapeutic agent, cells were treated with melphalan, a chemotherapeutic agent currently in clinical trials to treat Rb. Preliminary data with the Rb 143 cell line treated with melphalan show that Survivin expression is downregulated while Hsp27 expression is upregulated with increasing doses of melphalan. Previous studies with etoposide support the dose-dependent upregulation of Hsp27 following etoposide treatment in Rb143 cells. In order to examine the importance of Survivin and Hsp27 expression, apoptotic events will be correlated to Survivin and Hsp expression via flow cytometry after treatment with melphalan. Ongoing studies are focused on examining additional cell lines to determine whether Survivin and Hsp27 are alternately regulated in other Rb cell lines. In order to examine the importance of Survivin and Hsp27 expression, each protein will be independently downregulated with siRNA prior to treatment with melphalan. These studies may shed light on the mechanism of chemoresistance in Rb and have the potential to lead to novel treatment therapies for Rb targeting IAPs and small Hsps. Defining the mechanisms of resistance will provide new therapeutic targets for clinically difficult cases. If linked to chemoresistance, Survivin and Hsp27 can be downregulated prior to treatment, increasing the sensitivity of the tumor to chemotherapy.

Original Citation

Koch, M., Bowen, J.A., Galanis, Al, Gregory, M., Ksander, B.R., & Kreyosky, M.K. (2012). Role of Survivin and Small Heat Shock Proteins in the Chemoresistance of Retinoblastoma [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Research 72(8 Suppl):Abstract nr 2257. https://doi.org/10.1158/1538-7445.AM2012-2257