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Antisense Suppression of Proline-directed Protein Kinase F_A Enhances Chemosensitivity in Human Prostate Cancer Cells¹

Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan 30013 Republic of China

Initial clinic studies revealed that proline-directed protein kinase F_A (PDPK F_A) is overexpressed manyfold in various human cancerous tissues relative to the normal control. However, the role of overexpressed PDPK F_A in cancers remains unknown and needs to be established. To determine whether PDPK F_A is associated with drug sensitivity, we investigated the effects of partial inhibition of this kinase on the human prostate carcinoma cell line (PC-3). PDPK F_A antisense expression vector and its specific antibody were successfully developed. Two stable transfected antisense clones (PA7 and PA3) of human prostate carcinoma cell were subcloned, and they expressed 75% and 35% of the total PDPK F_A existing in the control-transfected clone as determined by both immunoprecipitate activity assay and immunoblot analysis. In sharp contrast, the PDPK F_A antisense clones expressed no significant suppression of any other related proline-directed protein kinase member expression, demonstrating the specificity of these two antisense clones. When compared with parental or control-transfected cells, the low-PDPK F_A-expressing antisense clones displayed an enhanced sensitivity to carboplatin, 5-fluorouracil, paclitaxel, and hydroxyurea. Estimation of the IC₅₀ index further revealed that the antisense clones displayed up to >100-fold drug sensitivity, and there was a correlation between suppressed levels of PDPK F_A and drug sensitivity. Taken together, the results demonstrate that specific antisense suppression of overexpressed PDPK F_A in human prostate cancer cells is sufficient to enhance various drug sensitivity, indicating that PDPK F_A is an important regulator in controlling multiple drug resistance of human prostate cancer cells.

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