Association of overexpressed proline-directed protein kinase F(A) with chemoresistance, invasion, and recurrence in patients with bladder carcinoma

• Published in: Cancer 2002-08, Vol.95 (4), p.775-783
• Main Authors: Hsueh, Sheng-Fen, Lai, Ming-Tsung, Yang, Chuan-Ching, Chung, Yuan-Chiang, Hsu, Chih-Ping, Peng, Chien-Chung, Fu, Hsiao-Hui, Cheng, Yung-Ming, Chang, King-Jen, Yang, Shiaw-Der
• Format: Article
• Language: English
• Subjects: Adult; Aged; Calcium-Calmodulin-Dependent Protein Kinases - biosynthesis; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Glycogen Synthase Kinase 3; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Prognosis; Tumor Cells, Cultured; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - enzymology; Urinary Bladder Neoplasms - pathology
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.10731

It has been shown previously that proline-directed protein kinase F(A) (PDPK F(A)) is overexpressed in various human malignancies compared with its expression in normal controls, and the suppression of overexpressed PDPK F(A) is capable of inhibiting the growth of various types of human carcinoma cells, suggesting a role for this PDPK in human malignancies. In this report, the authors combine immunohistologic, molecular, cellular, and clinicopathologic studies to demonstrate further an essential critical role for overexpressed PDPK F(A) in bladder carcinoma invasion, chemoresistance, and poor prognosis. The expression and localization of PDPK F(A) were analyzed by the immunohistochemical staining of specimens obtained from patients with primary transitional cell carcinoma (TCC) of the bladder. The stable antisense clones of human bladder carcinoma cells with specific suppression of overexpressed PDPK F(A) were established for invasion and chemosensitivity studies. The immunohistochemical study revealed that PDPK F(A) was overexpressed preferentially in the invasive bladder carcinoma tissues. It was found that the stable antisense clones with specific suppression of overexpressed PDPK F(A) to approximately 40% of the parental control level were capable of inhibiting the invasive activity and simultaneously enhancing the chemosensitivity of bladder carcinoma cells to various therapeutic drugs, such as vinblastine, vincristine, paclitaxel, and bleomycin. Clinicopathologic studies also revealed a correlation between overexpressed PDPK F(A) and disease recurrence/survival in patients with primary TCC (P < 0.05). Taken together, the results demonstrate an essential critical role of overexpressed PDPK F(A) in invasion, chemoresistance, and poor prognosis. Suppression of overexpressed PDPK F(A) may provide a new potential target for therapeutic intervention aimed at preventing chemoresistance, disease progression, and recurrence in patients with bladder carcinoma.