Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function

Polo-like kinase 1 (PLK1), which has been shown to have a critical role in mitosis, is one possible target for cancer therapeutic intervention. PLK1, at least in Xenopus, starts the mitotic cascade by phosphorylating and acti vating cdc25C phosphatase. Also, loss of PLK1 function has been shown to in duce mitotic catastrophe in a HeLa cervical carcinoma cell line but not in normal Hs68 fibroblasts. We wanted to understand whether the selective mito tic catastrophe in HeLa cells could be extended to other tumor types, and, if so, whether it could be attributable to a tumor-specific loss of depende nce on PLK1 for cdc25C activation. When PLK1 function was blocked through a denovirus delivery of a dominant-negative gene, we observed tumor-selective apoptosis in most tumor cell lines. In some lines, dominant-negative PLK1 induced a mitotic catastrophe similar to that published in HeLa cells (K. E . Mundt et al., Biochem. Biophys Res. Commun., 239: 377-385, 1997). Normal human mammary epithelial cells, although arrested in mitosis, appeared to e scape the loss of centrosome maturation and mitotic catastrophe seen in tum or lines. Mitotic phosphorylation of cdc25C and activation of cdk1 was bloc ked by dominant-negative PLK1 in human mammary epithelial cells as well as in the tumor lines regardless of whether they underwent mitotic catastrophe . These data strongly argue that the mitotic catastrophe is not attributabl e to a lack of dependence for PLK1 in activating cdc25C.