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NUCLEAR RECEPTORS, ROS & CANCER BIOLOGY

DIANA HAY HUI SIN, BSc. (Hon) Postgraduate Student National University Medical Institutes MD11, 10 Medical Drive, #B1-07 Email: g0700058@nus.edu.sg Major Supervisor: Dr. Alan Prem Kumar Co-supervisors: Prof. Shazib Pervaiz and A/Prof. Martin Lee Tel: (65) 6516-4445 Fax: (65) 6773-5461

DP103 is a member of the DEAD-box family of helicases, distinguished by a characteristic amino acid sequence Asp-Glu-Ala-Asp (DEAD). Members in this family have been shown to have important roles in cell development, differentiation and proliferation. DP103 was found to be strongly expressed in primary human malignant melanomas and epithelial elements of developing nephrons of the kidney. It had been shown that DP103 is required for mitogenic ETS (METS) repressor activity in Ras-dependent proliferation and for mediating apoptosis through FOXL2, a forkhead family transcriptional factor. In our study, we seek to identify a role of DP103 in proliferation and apoptosis in cancer and developing kidney, using a human malignant melanoma cell line and a human embryonic kidney cell line as models through loss-of-function and gain-of-function experiments. We show that specific knockdown of DP103 in the malignant melanoma cell line increased cell viability and proliferation. Conversely, overexpression of DP103 decreased cell viability and proliferation and increased the percentage of cells entering apoptosis. Together, our results showed that DP103 has anti-proliferative and pro-apoptotic activity in cancer cells as well as in the developing kidneys. Our Group has previously established that one possible mechanism involved in the regulation of tumor cell response to apoptosis could be linked to the ratio of intracellular O2- to H2O2. Our data have demonstrated that an increase in intracellular O2- inhibits tumor cell apoptosis triggered by anticancer drugs. On the contrary, production of intracellular H2O2 was shown to sensitize tumor cells to apoptotic triggers. In our present study, we therefore ask if the cells’ fate to absence of over-expression of DP103 is a function of a ratio in intracellular O2- to H2O2.