Superior inhibitory efficacy of butyrate over propionate and acetate against human colon cancer cell proliferation via cell cycle arrest and apoptosis: linking dietary fiber to cancer prevention

Abstract

Intake of dietary fiber may protect against colon cancer. The anticancer property is associated with an increased production of short chain fatty acids (SCFAs), including acetate, propionate and butyrate, during dietary fiber fermentation in the colon. However, the mechanisms remain to be determined. We hypothesized that butyrate exhibits a stronger inhibitory potential against colon cancer cell proliferation compared with acetate and propionate. We determined the half maximal inhibitory concentrations (IC50) of SCFAs in HCT116 human colon cancer cell proliferation by examining cell growth curves. At 24- and 48-hour time points, IC50 (mmol/L) concentrations of acetate, propionate, and butyrate were [66.0 and 29.0], [9.2 and 3.6], and [2.5 and 1.3], respectively. Consistent with the greater anti-proliferative effect, butyrate exhibits >3-fold stronger potential for inducing cell cycle arrest at the G2 phase with a drop in S-phase fraction (including c-Myc/p21 signaling) and apoptosis when compared with acetate and propionate. Subsequently, we focused on the effect of butyrate on apoptotic gene expression. Using a PCR array analysis, we identified 17 pro-apoptotic genes, 6 anti-apoptotic genes, and 4 cellular mediator genes with >1-fold increase or decrease in mRNA levels out of 93 apoptosis related genes in butyrate-treated HCT116 cells when compared with untreated HCT116 cells. These genes were mainly involved in the TNF, NFκB, CARD, and BCL-2 regulated pathways. Taken together, our data indicate a greater inhibitory efficacy of butyrate over propionate and acetate against human colon cancer cell proliferation via cell cycle arrest and apoptosis.