Oncotarget

Research Papers:

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

Yun-Jeong Jeong, Hyun-Ji Cho, Fung-Lung Chung, Xiantao Wang, Hyang-Sook Hoe, Kwan-Kyu Park, Cheorl-Ho Kim, Hyeun-Wook Chang, Sang-Rae Lee and Young-Chae Chang _

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Oncotarget. 2017; 8:63949-63962. https://doi.org/10.18632/oncotarget.19213

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Abstract

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

Correspondence to:

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

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.


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