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Nutrition and Cancer

Prolonged Butyrate Treatment Inhibits the Migration and Invasion Potential of HT1080 Tumor Cells¹

U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034

²To whom correspondence should be addressed. E-mail: hzeng{at}gfhnrc.ars.usda.gov.

Butyrate, a normal constituent of the colonic luminal contents, is produced by the bacterial fermentation of dietary fibers and resistant starches. It has been hypothesized that butyrate may inhibit the invasion of tumor cells. The purpose of the present study was to investigate the effects of butyrate treatment on the growth, migration, and invasion characteristics of tumor HT1080 cells. HT1080 cells cultured in the presence of 0.5 and 1 mmol/L butyrate for 14 d exhibited an increase in the G₁ and G₂ fractions with a concomitant drop in the S-phase, thus showing slower cell growth. Interestingly, 0.5 and 1 mmol/L butyrate inhibited the migration and invasion rate of the tumor cells compared with the untreated (control) cells. The protein and mRNA levels of the tissue inhibitors of metalloproteinase-1 (TIMP-1) and TIMP-2 were significantly increased in HT1080 cells cultured with 0.5 and 1 mmol/L butyrate. Enzymatic activities and the mRNA level of the latent forms of matrix metalloproteinase (MMP), pro-MMP-2 and pro-MMP-9, were also increased in HT1080 cells cultured with 0.5 and 1 mmol/L butyrate. In contrast, the active form of MMP-2 was detectable by zymographic analysis in control but not butyrate-conditioned media. Collectively, these results demonstrate that prolonged and low-dose butyrate treatment increases both prometastasis MMP-2, -9 and antimetastasis TIMP-1, -2 expression, and the net effect of these increases is the inhibition of pro-MMP-2 activation and of tumor cell migration/invasion potential.

KEY WORDS: • butyrate • cell cycle • migration • invasion • cancer

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