Butyrate has antitumorigenic effects on
colon cancer cells, inhibits cell growth and promotes differentiation and apoptosis. These effects depend on its intracellular concentration, which is regulated by its transport. We have analysed
butyrate uptake kinetics in human
colon adenocarcinoma cells sensitive to the apoptotic effects of
butyrate (BCS-TC2, Caco-2 and HT-29), in
butyrate-resistant cells (BCS-TC2.BR2) and in normal colonic cells (FHC). The properties of transport were analysed with structural analogues, specific inhibitors and different
bicarbonate and
sodium concentrations. Two carrier-mediated mechanisms were detected: a low-affinity/high-capacity (K(m)=109+/-16 mM in BCS-TC2 cells)
anion exchanger and a high-affinity/low-capacity (K(m)=17.9+/-4.0 microM in BCS-TC2 cells)
proton-monocarboxylate
co-transporter that was energy-dependent and activated via PKCdelta (
protein kinase Cdelta). All
adenocarcinoma cells analysed express MCT (monocarboxylate transporter) 1, MCT4, ancillary
protein CD147 and
AE2 (anion exchanger 2). Silencing experiments show that MCT1, whose expression increases with
butyrate treatment in
butyrate-sensitive cells, plays a key role in high-affinity transport. Low-affinity uptake was mediated by a
butyrate/
bicarbonate antiporter along with a possible contribution of AE2 and MCT4.
Butyrate treatment increased uptake in a time- and dose-dependent manner in
butyrate-sensitive but not in
butyrate-resistant cells. The two
butyrate-uptake activities in human
colon adenocarcinoma cells enable
butyrate transport at different physiological conditions to maintain cell functionality. The high-affinity/low-capacity transport functions under low
butyrate concentrations and may be relevant for the survival of
carcinoma cells in tumour regions with low
glucose and
butyrate availability as well as for the normal physiology of colonocytes.