Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells

Abstract

Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally occurring flavonoid, has been reported to possess some anti-cancer and anti-inflammation capabilities. In this study, fisetin has exhibited inhibitory effects on the adhesion, migration, and invasion ability of a highly metastatic PC-3 cells under non-cytotoxic concentrations. Gelatin zymography assay showed that fisetin inhibited the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activities. Our result also showed that fisetin could inhibit the phosphorylation of c-Jun N-terminal kinase 1 and 2 (JNK1/2) and Akt. Moreover, fisetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun, and the binding abilities of NF-kappaB and activator protein-1 (AP-1). Also, the results showed that the protein and mRNA levels of MMP-2 and MMP-9 were significantly reduced by Western blot and semi-quantitative RT-PCR. Further, treating specific inhibitors for PI3K (Wortmannin) or JNK (SP600125) to PC-3 cells could reduce the protein expressions of MMP-2 and MMP-9. These results showed fisetin could inhibit the metastatic ability of PC-3 by reducing MMP-2 and MMP-9 expressions through suppressing phosphoinositide 3-kinase/Akt (PI3K/Akt) and JNK signaling pathways. This suggested fisetin can serve as a potential candidate for treating cancer metastasis.

Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by apigenin via the inhibition of p38 mitogen-activated protein kinase-dependent matrix metalloproteinase-9 expression

“…Recently, considerable attention has been devoted to identifying plant-derived dietary agents that interfere with tumor metastasis via inhibiting MMP-9 expression and activity because of their non-toxicity and biocompatibility (13,(19)(20)(21)(22). It has been reported that low-molecular-weight apigenin is useful in preventing tumor growth in many different types of human cancers (13,23,24).…”

Naringenin modulates the metastasis of human prostate cancer cells by down regulating the matrix metalloproteinases -2/-9 via ROS/ERK1/2 pathways

“…The intensity of expression of MMP-2 and MMP-9 is associated with the degree of prostate cancer progression (Stearns and Stearns, 1995;Nemeth, 2002). Thus blocking tumor cell expression/ inhibition of MMP-2/-9 could possibly suppress tumour invasion and metastasis of prostate cancer (Chien et al, 2010;Kong et al, 2007). Various plants and plant extracts have been explored widely in the treatment of cancer.…”

Flavonoids from Artemisia sacrorum Ledeb. and their cytotoxic activities against human cancer cell lines

“…The results demonstrated that this fraction was markedly rich in flavonoids. Flavonoids are cancer-preventive agents, and have been shown to be particularly important (16)(17)(18). Therefore, the present study was further conducted to evaluate the cytotoxic activities of all flavonoids from the CH 2 Cl 2 and 95% EE fractions.…”