Abstract
The forkhead box protein O1 (FOXO1) is considered to be a key tumor suppressor due to its involvement in a broad range of cancer-related functions, including cellular differentiation, apoptosis, cell cycle arrest, and DNA damage. Given that inactivation of FOXO1 has been reported in many types of human cancer, we sought to investigate whether restoration of the pro-apoptotic activity of FOXO1 may be used as a new promising strategy for cancer treatment. Our previous study revealed that Polo-like kinase 1 (PLK1), a serine/threonine kinase that is essential for cell cycle progression, is a novel and major regulator of FOXO1 in the late phases of the cell cycle. Here, we provided evidence that PLK1-dependent phosphorylation of FOXO1 induces its nuclear exclusion and negatively regulates FOXO1′s transcriptional activity in prostate cancer (PCa). Blocking the PLK1-dependant phosphorylation of FOXO1 restored the pro-apoptotic function of FOXO1 in PCa. Combining PLK1 inhibition with nocodazole (to induce mitotic arrest) had synergistic antitumor effects in vitro, with minimal effect on normal prostate epithelial cells. These findings shed light on a novel approach to reactivate apoptotic pathways in advanced PCa and support targeting PLK1-FOXO1 pathways as a novel approach for treating advanced PCa.
Highlights
The transcriptional activity of FOXO1 is inhibited by Polo-like kinase 1 (PLK1)‐mediated phosphorylation in Prostate cancer (PCa) cells
We previously demonstrated that PLK1 phosphorylates FOXO1, which promotes the inhibition of
Using a luciferase-based FOXO1 transcriptional activity reporter plasmid, we investigated whether PLK1 phosphorylation of FOXO1 causes the inhibition of FOXO1 transcriptional activity in PCa cells
Summary
PLK1 binds to and phosphorylates FOXO1 during the late phase of the cell cycle. This phosphorylation event induced the nuclear exclusion of FOXO1 and, led to the inhibition of FOXO1′s transcriptional activity in the late phases of the cell cycle[18]. We reported that blocking PLK1-dependant phosphorylation of FOXO1 delays G 2/M transition and promotes the activation of pro-apoptotic signaling pathways, leading to cell death[18]. We set out to investigate the potential involvement of the PLK1-FOXO1 pathway in human PCa and to explore the therapeutic potential of this regulation. We show that PLK1-mediated phosphorylation of FOXO1 induces its nuclear exclusion, leading to the inhibition of FOXO1′s nuclear transcriptional activity in PCa cells.
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