Isothiocyanates, which are present as
glucosinolate precursors in cruciferous vegetables, have strong activity against various
cancers. Here, we compared the anti-metastatic effects of
isothiocyanates (
benzyl isothiocyanate (BITC),
phenethyl isothiocyanate (
PEITC), and
sulforaphane (SFN)) by examining how they regulate MMP-9 expression.
Isothiocyanates, particularly
PEITC, suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 activity and invasion in various
cancer cell lines. By contrast, N-methyl
phenethylamine, a
PEITC analog without an
isothiocyanate functional group, had no effect. A reporter gene assay demonstrated that BITC,
PEITC, and SFN suppressed TAP-induced MMP-9 expression by inhibiting
AP-1 and NF-κB in U20S
osteosarcoma cells. All three compounds reduced phosphorylation of FAK, ERK1/2, and Akt. In addition, MMP-9 expression was downregulated by inhibiting FAK, ERK1/2, and Akt.
Isothiocyanates-mediated inhibition of FAK phosphorylation suppressed phosphorylation of ERK1/2 and Akt in U2OS and A549 cells, along with the translocation of p65 and c-Fos, suggesting that
isothiocyanates inhibit MMP-9 expression and cell invasion by blocking phosphorylation of FAK. Furthermore,
isothiocyanates, abolished MMP-9 expression and
tumor metastasis in vivo with the following efficacy:
PEITC>BITC>SFN. Thus,
isothiocyanates act as anti-metastatic compounds that suppress MMP-9 activity/expression by inhibiting NF-κB and
AP-1 via suppression of the FAK/ERK and FAK/Akt signaling pathways.