Curcumol Suppresses Breast Cancer Cell Metastasis by Inhibiting MMP-9 Via JNK1/2 and Akt-Dependent NF-κB Signaling Pathways

Abstract

Curcumolhas been reported to possess antitumor activity. However, its effect and mechanisms against tumor metastasis are still unclear. This study is to investigate the inhibitory effect of curcumol on breast cancer cell metastasis and elucidate the underlying molecular mechanisms. Our results showed that noncytotoxicity was caused by curcumol within 10 to 40 µg/mL in MDA-MB-231 and 4T1 cells for 24 hours, whereas sustained treatment with curcumol for 14 days significantly suppressed the clonogenic activity of cells. Importantly, curcumol at noncytotoxic concentrations suppressed the migration ability of both MDA-MB-231 and 4T1 cells. Moreover, curcumol suppressed the migration and invasion of MDA-MB-231 cells in the Boyden chamber migration and invasion assay and inhibited the adhesion of MDA-MB-231 cells onto the matrigel. Further investigations revealed that curcumol decreased the enzyme activity and protein expression of matrix metalloproteinase (MMP-9) in MDA-MB-231 cells. Moreover, curcumol inhibited the activation of c-Jun N-terminal kinase (JNK) 1/2 and Akt (Ser473). Meanwhile, it also inhibited the nuclear translocation and transcriptional activity of nuclear factor κB (NF-κB). Furthermore, JNK inhibitor SP600125 and Akt (Ser473) inhibitor LY294002 enhanced the inhibition of curcumol on NF-κB p65 nuclear translocation. Finally, supplementation with SP600125, LY294002, or NF-κB inhibitor Ammonium pyrrolidinedithiocarbamate (PDTC) significantly enhanced the inhibitory effect of curcumol on MMP-9 expression and cell migration, invasion, and adhesion in MDA-MB-231 cells. Our findings provide evidence for the suppression of breast cancer cell metastasis by curcumol and suggest that the inhibition of MMP-9 via JNK1/2 and Akt (Ser473)-dependent NF-κB signaling pathways may be the underlying mechanisms.