Proline-directed protein kinase FA as a potential target for diagnosis and therapy of human cancers.

Proline-directed protein kinase FA (PDPK FA) was originally identified as a phosphatase activating factor (FA) but has subsequently been characterized as a multisubstrate/multifunctional PDPK possibly associated with human cancers. In recent years, the immunohistochemical study revealed that PDPK FA was highly expressed in tumor mass and preferentially overexpressed in the invasive lesions of the resected tissue sections obtained from various types of cancer patients. The clinicopathologic study further revealed a close correlation of the overexpression of PDPK FA with poor prognosis of the cancer patients. The antisense gene therapy study also confirmed that due to its multisubstrate/multifunctional PDPK nature, the overexpression of PDPK FA is essential for the development of malignant growth, tumorigenesis, invasion, metastasis, anti-differentiation, anti-apoptosis and chemoresistance in human cancers. From immunohistochemical, clinicopathologic and antisense gene therapeutic studies combined together, PDPK FA has emerged as a key regulator of all aspects of neoplasia. In this way, nature provides prima facie evidence of a particular protein kinase's pivotal importance to the neoplastic state. PDPK FA therefore represents a newly-described, previously-undiscovered novel signal transducing target for diagnosis, disease monitoring, drug screening and therapy of human cancers.

Suppression of proline-directed protein kinase F(A) inhibits the malignant growth of human pancreatic ductal adenocarcinoma.

BACKGROUND: Proline-directed protein kinase F(A) (PDPK F(A)) was originally identified as a specific phosphatase activating factor, but has subsequently been demonstrated as a multisubstrate PDPK possibly involved in the regulation of diverse malignant characteristics of various types of human cancers including prostate, leukemia, bladder and colon cancers. However, the role of this PDPK in a lethal carcinoma, such as pancreatic ductal adenocarcinoma, remains to be established. MATERIALS AND METHODS: The stable antisense clones with specific suppression of overexpressed PDPK F(A) of human pancreatic ductal adenocarcinoma cells (MIA PaCa-2) were first selected and subsequently characterized for the in vitro and in vivo growth studies. RESULTS: The molecular and cellular studies revealed that the antisense clones of MIA PaCa-2 cells with specific suppression of overexpressed PDPK F(A) potentially exhibited cell growth retardation, decreased serum independence, poor clonogenic growth and loss of anchorage-independent growth. The in vivo study further confirmed that the SCID mice injected with the antisense clones with low-level PDPK F(A) did not develop any detectable tumors even after 7-week observation. In sharp contrast, the parental or control-transfected clones developed very large tumors (>5 cm3) under identical conditions. CONCLUSION: The molecular, cellular and animal results taken together demonstrate that overexpressed PDPK F(A) is essential for the malignant growth of human pancreatic ductal adenocarcinoma.