Association of overexpressed proline-directed protein kinase Fa with chemoresistance, invasion, and recurrence in patients with bladder carcinoma

Abstract

BACKGROUND. It has been shown previously that proline-directed protein kinase FA (PDPK FA) is overexpressed in various human malignancies compared with its expression in normal controls, and the suppression of overexpressed PDPK FA 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 FA in bladder carcinoma invasion, chemoresistance, and poor prognosis. METHODS. The expression and localization of PDPK FA 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 FA were established for invasion and chemosensitivity studies. RESULTS. The immunohistochemical study revealed that PDPK FA was overexpressed preferentially in the invasive bladder carcinoma tissues. It was found that the stable antisense clones with specific suppression of overexpressed PDPK FA to ≈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 FA and disease recurrence/survival in patients with primary TCC (P < 0.05). CONCLUSIONS. Taken together, the results demonstrate an essential critical role of overexpressed PDPK FA in invasion, chemoresistance, and poor prognosis. Suppression of overexpressed PDPK FA may provide a new potential target for therapeutic intervention aimed at preventing chemoresistance, disease progression, and recurrence in patients with bladder carcinoma. © 2002 American Cancer Society.