SHORT-CHAIN FATTY-ACIDS INHIBIT HUMAN (SW1116) COLON-CANCER CELL INVASION BY REDUCING UROKINASE PLASMINOGEN-ACTIVATOR ACTIVITY AND STIMULATING TIMP-1 AND TIMP-2 ACTIVITIES, RATHER THAN VIA MMP MODULATION

Background. Short chain fatty acids derived from dietary fiber may pro tect against invasive colon cancer by modulating degradative matrix me talloproteinases (MMPs) and protective tissue inhibitor matrix metallo proteinases (TIMPs). Since invasion depends on the MMP/TIMP ratio, we hypothesized that short chain fatty acids inhibit colon cancer invasio n by inhibiting MMPs and stimulating TIMPs. Materials and methods. SW1 116 colon cancer cells were seeded onto Matrigel-coated Boyden chamber s and treated with unsupplemented media or media containing 10 mM acet ate, propionate, or butyrate. SW1116 invasion was quantitated by light microscopy and conditioned media were assayed by ELISA for MMP-1,2,3, 9; TIMP-1,2; MMP/TIMP complex; and urokinase plasminogen activator (uP A). All data are expressed as mean percentage of control +/- SE (n > 6 ). Results. Although all three short chain fatty acids inhibited invas ion, butyrate was more potent than either acetate or propionate, inhib iting SW1116 invasion by 35 +/- 1% of control (n = 18, P < .0001) vs. 18 +/- 9% (n = 7, P < .05) for acetate and 10 +/- 6% (n = 7, P < .05) for propionate. MMP-2 was not modulated by any of the short chain fatt y acids while MMP-1 was modulated only by butyrate and MMP-3 by propio nate. Acetate did not modulate MMPs, TIMP-1, or uPA, but stimulated TI MP-2. In contrast, propionate and butyrate stimulated MMP-9 and TIMP-2 by 119-233% and both inhibited uPA by 8-16%. TIMP-1 was stimulated on ly by butyrate and actually inhibited by propionate. Only butyrate sti mulated both TIMP-1 and TIMP-2. Conclusions. These data suggest that d ietary fiber may protect against invasive colon cancer through stimula tion of TIMP and inhibition of uPA activities, rather than through sho rt chain fatty acids effects on the activities of the MMPs studied. (C ) 1998 Academic Press.