Isothiocyanates suppress the invasion and metastasis of tumors by targeting FAK/MMP-9 activity

// Yun-Jeong Jeong 1, * , Hyun-Ji Cho 1, 2, * , Fung-Lung Chung 3, * , Xiantao Wang 3, 4 , Hyang-Sook Hoe 2 , Kwan-Kyu Park 1 , Cheorl-Ho Kim 5 , Hyeun-Wook Chang 6 , Sang-Rae Lee 7 and Young-Chae Chang 1 1 Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea 2 Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 701-300, Republic of Korea 3 Department of Oncology, Lambardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA 4 National Institutes of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA 5 Department of Biological Science, Sungkyunkwan University, Suwon, Kyunggi-Do 440-746, Republic of Korea 6 College of pharmacy, Yeungnam University, Gyeongsan 701-947, Republic of Korea 7 National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungbuk 28116, Republic of Korea * These authors have contributed equally to this work Correspondence to: Young-Chae Chang, email: ycchang@cu.ac.kr Sang-Rae Lee, email: srlee@kribb.re.kr Keywords: isothiocyanates, metastasis, cancer invasion, MMP-9, FAK Received: September 28, 2016      Accepted: June 10, 2017      Published: July 12, 2017 ABSTRACT 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.