title: PEA-15 unphosphorylated at both serine 104 and serine 116 inhibits ovarian cancer cell tumorigenicity and progression through blocking β-catenin.
abstract: 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 β-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.
authors.affiliation: 1] Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Bartholomeusz
authors.forename: S
authors.initials: S
authors.lastname: Krishnamurthy
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Saso
authors.forename: T A
authors.initials: TA
authors.lastname: Lafortune
authors.forename: G N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: N T
authors.initials: NT
authors.lastname: Ueno
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