Abstract
Inactivation of p53 greatly contributes to serous ovarian cancer, while the role of the wild-type p53 induced phosphatase 1 (Wip1) is quite unclear. In this study, by silencing or overexpression of Wip1, we found that Wip1 suppressed ovarian cancer cell invasion, migration, epithelial to mesenchymal transition (EMT), and ovarian cancer metastasis in xenograft animal models. Mechanistic studies showed that Wip1 may block ovarian cancer metastasis through inhibition of Snail and p-Akt expression because silencing or overexpression of Wip1 either upregulated or downregulated the expression of Snail and p-Akt (Ser 473), while further knockdown of Snail by shRNA or inhibition of p-Akt by a chemical compound attenuated cell invasion, migration and EMT in Wip1 silencing cells. We also found that the phosphorylation of Akt at Ser 473 might be mediated through p-ATM (Ser 1981). Thus, Wip1 may suppress ovarian cancer metastasis through negative regulation of p-ATM, p-Akt, and Snail, which was also evidenced in the limited clinical specimens. Therefore, our data may provide a novel therapeutic indication for serous ovarian cancer based on the uncovered mechanism associated with the precise function of Wip1 independent of p53.
Highlights
Ovarian cancer is the eighth most common cancer in women and the leading cause of death from gynecological malignancies in developed countries [1]
We found that knockdown of wild-type p53 induced phosphatase 1 (Wip1) increased cell migration (Figure1C and Figure 1D) and invasion (Figure 1E), indicating that Wip1 may suppress cell invasion and migration in serous ovarian cancer cells
Since knockdown of snail and inhibition of the Akt/ GSK-3β signaling inhibited the motility of cells with Wip1 knockdown, we propose that Akt, GSK-3β, and snail are downstream targets of Wip1, while ATM may link Wip1 with the Akt/GSK-3β/snail signaling (Figure 8)
Summary
Ovarian cancer is the eighth most common cancer in women and the leading cause of death from gynecological malignancies in developed countries [1]. According to the American Cancer Society (Atlanta, GA), 21,980 new ovarian cancer cases were diagnosed in 2014, and the 5-year survival was around 44% [2]. 70% of ovarian cancer patients are diagnosed at the stage of FIGO III/IV with widespread cancer cells beyond ovaries. Despite surgical and chemotherapeutic improvements, most patients may eventually relapse and have poor prognosis after primary treatment. Numerous studies have demonstrated that EMT is associated with the motility or invasion of ovarian carcinoma. The detailed mechanism of EMT in ovarian cancer has yet to be defined
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