Isothiocyanates suppress the invasion and metastasis of tumors by targeting FAK/MMP-9 activity
Metrics: PDF 2204 views | HTML 3837 views | ?
Yun-Jeong Jeong1,*, Hyun-Ji Cho1,2,*, Fung-Lung Chung3,*, Xiantao Wang3,4, Hyang-Sook Hoe2, Kwan-Kyu Park1, Cheorl-Ho Kim5, Hyeun-Wook Chang6, Sang-Rae Lee7 and Young-Chae Chang1
1Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea
2Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 701-300, Republic of Korea
3Department of Oncology, Lambardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
4National Institutes of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
5Department of Biological Science, Sungkyunkwan University, Suwon, Kyunggi-Do 440-746, Republic of Korea
6College of pharmacy, Yeungnam University, Gyeongsan 701-947, Republic of Korea
7National 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
Young-Chae Chang, email: [email protected]
Sang-Rae Lee, email: [email protected]
Keywords: isothiocyanates, metastasis, cancer invasion, MMP-9, FAK
Received: September 28, 2016 Accepted: June 10, 2017 Published: July 12, 2017
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.