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KMID : 0613820170270091020
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Journal of Life Science
2017 Volume.27 No. 9 p.1020 ~ p.1030
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ω3-Polyunsaturated Fatty Acids-induced Inhibition of Tumorigenicity and Invasion by Suppression of COX-2/MMPs/VEGF through NF-kB in Colon Cancer Cells
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Shin So-Yeon
Kim Yong-Jo
Han Seung-Hyeon
Prashanta Silwal
Heo Jun-Young
Jeon Young-Joo
Park Seung-Gil
Kwon Gi-Ryang
Park Jong-Il
Im Kyu
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Abstract
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Epidemiology studies have reported a reduced incidence of colon cancer among populations that consume a large quantity of ω3-polyunsaturated fatty acids (ω3-PUFAs) of marine origin. Herein, we demonstrated a mechanism of anticancer action of ω3-PUFAs, showing that they suppressed invasion and tumorigenicity in colon cancer cells. Docosahexaenoic acids (DHA) inhibited the cell growth of HT29 cells. This action likely involved apoptosis, given that the DHA treatment increased the cleaved form of PARP and sub G1 cells. Moreover, the invasiveness of HT29 cells was inhibited following DHA treatment, whereas arachidonic acid (AA) had no effect. The levels of Matrix-metalloproteinase-9 (MMP-9) and MMP-2 mRNA decreased after DHA pretreatment. DHA treatment inhibited MMP-9 and MMP-2 promoter activities and reduced VEGF promoter activity. DHA pretreatment also inhibited the activities of prostaglandin-2 (PGE2)-induced MMPs and the VEGF promoter. Cyclooxygenase-2 (COX-2) overexpression increased the activity of MMPs and that of the Vascular endotherial growth factor (VEGF) promoter in HT29 cells, and DHA inhibited NF-kB and COX-2 promoter reporter activities. As shown by in vivo experiments, when mouse colon cancer cells (MCA38) were implanted into Fat-1 and wild-type mice, both the tumoral size and volume were dramatically inhibited in Fat-1 transgenic mice. Furthermore, TUNEL-positive cells increased in tumors from Fat-1 mice compared with wild mice. In immunohistochemistry, the intensity of CD31 in Fat-1 tumors was weaker. These findings suggest that ω3-PUFAs may inhibit tumorigenicity and angiogenesis as well as cancer cell invasion by suppression of COX-2, MMPs and VEGF via the reduction of NF-kB in colon cancer.
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KEYWORD
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COX-2, docosahexaenoic acid, invasion, matrix metalloproteinase, ω3-polyunsaturated fatty acids
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