Forkhead box O (FoxO)
transcription factors play an important role as
tumor suppressor in several human
malignancies. Disruption of FoxO activity due to loss of
phosphatase and
tensin homolog and activation of phosphatidylinositol-3
kinase (PI3K)/Akt are frequently observed in
prostate cancer.
Apigenin, a naturally occurring plant
flavone, exhibits antiproliferative and anticarcinogenic activities through mechanisms, which are not fully defined. In the present study, we show that
apigenin suppressed prostate
tumorigenesis in transgenic
adenocarcinoma of the mouse prostate (TRAMP) mice through the PI3K/Akt/FoxO-signaling pathway.
Apigenin-treated TRAMP mice (20 and 50 μg/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in
tumor volumes of the prostate as well as completely abolished distant organ
metastasis.
Apigenin treatment resulted in significant decrease in the weight of genitourinary apparatus (P < 0.0001), dorsolateral (P < 0.0001) and ventral prostate (P < 0.028), compared with the control group.
Apigenin-treated mice showed reduced phosphorylation of Akt (Ser473) and FoxO3a (Ser253), which correlated with its increased nuclear retention and decreased binding of FoxO3a with 14-3-3. These events lead to reduced proliferation as assessed by Ki-67 and
cyclin D1, along with upregulation of FoxO-responsive
proteins BIM and p27/Kip1. Complementing in vivo results, similar observations were noted in human
prostate cancer LNCaP and PC-3 cells after
apigenin treatment. Furthermore, binding of FoxO3a with p27/Kip1 was markedly increased after 10 and 20 μM
apigenin treatment resulting in G0/G1-phase cell cycle arrest, which was consistent with the effects elicited by PI3K/Akt inhibitor,
LY294002. These results provide convincing evidence that
apigenin effectively suppressed
prostate cancer progression, at least in part, by targeting the PI3K/Akt/FoxO-signaling pathway.