Inhibitors of apoptosis are commonly expressed in many disorders, conferring cellular survival and resistance to death. The small heat shock protein aB-crystallin inhibits apoptosis by disrupting the activation of caspase-3, an enzyme that is critical for disassembly of the cell during apoptosis. While it is well established that aB-crystallin is expressed in the lens, crystallin proteins were recently identified in the retina, suggesting that these proteins may regulate retinal cell survival. Since aB-crystallin is expressed in several human cancers (breast, prostate and neuroblastoma) and is known to coincide with resistance to apoptosis induced by various chemotherapeutic agents, we predict that this heat shock protein may be important in the resistance to chemotherapy-induced apoptosis in retinoblastoma. Retinoblastoma, the most common eye cancer in children, can cause significant loss of vision and in some cases, is life-threatening. Current treatments use chemotherapy to reduce tumor size prior to irradiation. It is necessary to reduce the size of large tumors in order to keep the dose of irradiation within a range that can be tolerated by children. As such, resistance of retinoblastoma tumor cells to chemotherapy is a significant clinical problem. We hypothesize that expression of aB-crystallin in retinoblastoma cells confers resistance to chemotherapy-induced apoptosis by inhibiting caspase-3 mediated cell death, and that selective inhibition of this heat shock protein will restore chemosensitivity. This hypothesis will be tested in three specific aims (i) determine the expression of aB-crystallin in retinoblastoma tumor sections and in retinoblastoma cell lines; (ii) determine whether aB-crystallin inhibits apoptosis in retinoblastoma cells in vitro in response to various chemotherapeutic agents; (iii) determine whether specific inhibition of aB-crystallin makes retinoblastoma cells more susceptible to chemotherapy-induced apoptosis. These studies will identify a novel marker for chemotherapeutic resistance in retinoblastoma and will lead to future studies on novel treatment strategies that target aB-crystallin. Our long term goal is to prevent loss of vision and improve the quality of life for retinoblastoma patients. As an Academic Research Enhancement Award, this proposal will not only further research in retinoblastoma tumor cell biology, it will also advance the biological research training of qualified undergraduates at Bridgewater State College and expose future scientists to the exciting field of vision research. Merideth Kamradt Krevosky, R15 Academic Research Enhancement Award The role of aB-crystallin in chemoresistance of retinoblastoma Project Narrative: This is the first study in which the role of aB-crystallin in eye tumors will be studied. We will determine whether aB-crystallin prevents apoptotic cell death of retinoblastoma tumor cells induced by chemotherapeutic agents. If aB-crystallin mediates resistance to chemotherapy, this protein can be targeted and downregulated, making tumor cells more sensitive to treatment. Our long-term goal is to prevent loss of vision and to improve the quality of life for retinoblastoma patients. ? ? ?
