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 protect against invasive colon cancer by modulating degradative matrix metalloproteinases (MMPs) and protective tissue inhibitor matrix metalloproteinases (TIMPs). Since invasion depends on the MMP/TIMP ratio, we hypothesized that short chain fatty acids inhibit colon cancer invasion by inhibiting MMPs and stimulating TIMPs.


METHODS
SW1116 colon cancer cells were seeded onto Matrigel-coated Boyden chambers and treated with unsupplemented media or media containing 10 mM acetate, 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 (uPA). All data are expressed as mean percentage of control +/- SE (n > 6).


RESULTS
Although all three short chain fatty acids inhibited invasion, butyrate was more potent than either acetate or propionate, inhibiting 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 fatty acids while MMP-1 was modulated only by butyrate and MMP-3 by propionate. Acetate did not modulate MMPs, TIMP-1, or uPA, but stimulated TIMP-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 only by butyrate and actually inhibited by propionate. Only butyrate stimulated both TIMP-1 and TIMP-2.


CONCLUSIONS
These data suggest that dietary fiber may protect against invasive colon cancer through stimulation of TIMP and inhibition of uPA activities, rather than through short chain fatty acids effects on the activities of the MMPs studied.
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8062, USA.
N J
NJ
Emenaker
M D
MD
Basson
D000085:Acetates / Q000494:pharmacology; D000230:Adenocarcinoma; D002087:Butyrates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms; D004043:Dietary Fiber / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005232:Fatty Acids, Volatile / Q000494:pharmacology*; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D011422:Propionates / Q000494:pharmacology; D011480:Protease Inhibitors / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000085:Acetates; D002087:Butyrates; D004043:Dietary Fiber; D005232:Fatty Acids, Volatile; D011422:Propionates; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases