PEA-15 unphosphorylated at both serine 104 and serine 116 inhibits ovarian cancer cell tumorigenicity and progression through blocking ß-catenin.

Ovarian cancer is a major cause of death among women; there remains an urgent need to develop new effective therapies to target this cancer. Phosphoprotein enriched in astrocytes (PEA-15) is a 15-kDa phosphoprotein that is known to bind ERK1/2, thus blocking cell proliferation. The physiological activity of PEA-15 is dependent on the phosphorylation status of serine 104 (Ser104) and Ser116. However, little is known about the impact of PEA-15 phosphorylation on tumor progression. We have previously shown that overexpression of PEA-15 has an antitumor effect against both breast and ovarian cancer cells. Here, we report that using a human ovarian cancer tissue microarray, we found that tissues from patients with ovarian cancer were significantly more likely than adjacent normal tissues to express PEA-15 phosphorylated at both sites. Using phosphomimetic and nonphosphorylatable mutants of PEA-15, we found that mutant double-unphosphorylated PEA-15 in which Ser104 and Ser116 were substituted with alanine (PEA-15-AA) had a more potent antitumorigenic effect in ovarian cancer than did phosphomimetic PEA-15 in which Ser104 and Ser116 were substituted with aspartic acid (PEA-15-DD). Further, we observed that the antitumorigenic effect of PEA-15-AA was a result of inhibition of the migration capacity of cells and inhibition of in vivo angiogenesis. This inhibition was partially dependent on inhibition of ß-catenin expression and nuclear translocalization. Taken together, our results suggest that phosphorylated PEA-15 is an important contributor to the aggressiveness of ovarian cancer and justify the development of PEA-15-AA as an effective therapeutic molecule in the treatment of ovarian cancer.

Growth restriction of negative-strand-RNA viruses in a rat 3Y1 cell line.

A rat fibroblast cell line, 3Y1 is nonpermissive for infection by several negative-strand-RNA viruses including influenza virus A, Sendai virus, Newcastle disease virus and vesicular stomatitis virus (VSV), but not refractory to that of a positive-strand-RNA virus, Sindbis virus. To elucidate the mechanism of the restricted viral growth, we compared the replication pattern of VSV in 3Y1 cells and in baby hamster kidney cells, which are fully permissive for those viruses. The results indicated that the restriction was imposed predominantly on the transcription of the viral RNA. The subsequent steps such as protein synthesis and nucleocapsid assembly appeared to occur normally, although these levels remained low due to the restricted transcription. Virus attachment onto, and penetration into, 3Y1 cells were also not restricted.