Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, mutant p53, Bcl-2, Bax, p21 and PCNA protein expression in an in vitro cell culture model.
High intakes of dietary fiber or resistant starches have been associated with a lower incidence of colon cancers. Because short-chain fatty acids (SCFA) such as butyrate are produced in the colonic lumen by the bacterial fermentation of dietary fibers and resistant starches, we hypothesized that SCFA may inhibit the development of invasive human colon cancers. To test this hypothesis, primary human invasive colonocytes were isolated from fresh surgical specimens and treated with 0.01 mol/L acetate, propionate or butyrate; cell invasion, cell adhesion, F-actin polymerization, urokinase plasminogen activator (uPA), tissue inhibitor matrix metalloproteinase (TIMP)-1, TIMP-2 and mutant p53, Bcl-2, Bax, p21 and proliferating cell nuclear antigen (PCNA) protein expression levels were examined. Although each of the SCFA tested significantly reduced primary cell invasion, butyrate was the most potent, inhibiting primary invasive human colon cancer invasion by 54% (P < 0.0001). The effects of SCFA on primary cell invasion appeared to be independent of cell adhesion and F-actin polymerization but dependent on the inhibition of uPA (P < 0.05) and the stimulation of TIMP-1 and TIMP-2 activities (P < 0.05). Protein expression levels of mutant p53, p21, Bax, Bcl-2 and PCNA were significantly altered by each of the SCFA tested (P < 0.05). These data indicate that SCFA inhibit invasive human colon cancer by modulating proteolytic uPA and antiproteolytic TIMP-1 and TIMP-2 activities, but their mechanisms of action on tumor suppression, apoptosis and growth arrest may differ.
Emenaker
N J
NJ
Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY, USA. nje7@columbia.edu
Calaf
G M
GM
Cox
D
D
Basson
M D
MD
Qureshi
N
N
D000199:Actins / Q000737:chemistry / Q000187:drug effects; D000230:Adenocarcinoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D003106:Colon / Q000166:cytology; D003110:Colonic Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004043:Dietary Fiber / Q000378:metabolism; D005232:Fatty Acids, Volatile / Q000494:pharmacology*; D005260:Female; D005285:Fermentation; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D011108:Polymers; D019714:Tissue Inhibitor of Metalloproteinases / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D000199:Actins; D004043:Dietary Fiber; D005232:Fatty Acids, Volatile; D011108:Polymers; D019714:Tissue Inhibitor of Metalloproteinases; D014568:Urokinase-Type Plasminogen Activator