Improvement of Treatment for Urological Cancer by controlling Function of Apotosis-associated molecules using siRNA.

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1. XIAP knock down by siRNA or shRNA.Designed and introduction of XIAP siRNA or shRNA, decreased production of XIAP transiently or continuously, respectively.2. Prostate cancer model using DU145(1) Sensitivity to anticancer drug and knock down of XIAP expression.Transient suppression of XIAP resulted in increase susceptibility to CDDP, but continuous suppression induced resistant character than parent cell. Upregulation of BCL-2 and NF κ-B were observed in stable transfectants.(2) Restore the sensitivity by anti-BCL-2 small molecule HA14-1.HA14-1 cancelled decrease the susceptibility to CDDP.3. Renal cell cancer model using Caki-1.(1) XIAP and smac expression in normal kidney and renal cell cancer (RCC).In normal kidney, smac and XIAP were expressed in renal tubular cells. In 34 RCCs, smac was expressed less frequently, XIAP was strongly expressed in high grade and stage tumor. XIAP and smac were highly expressed in Caki-I and KRC/Y, respectively.(2) Effect of HA14-1 or smac-mimic synthetic peptide (smac-ant) on cell growth in Caki-1 XIAP lower expresser clone.HA14-1 alone revealed modest suppression of cell growth but combination with anti-Fas antibody resulted in additional effect-CDDP and smac-ant treatment showed high suppression.4. In conclusion, XIAP seems to decrease susceptibility to apoptotic stimuli in prostate and renal cell cancer. Suppression using shRNA may not be enough to overcome such character, and additional treatment for reduction of BCL-2 function or further suppression of XIAP using smac-ant might be useful.