The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter.
The orphan cotransport protein expressed by the SLC5A8 gene has been shown to play a role in controlling the growth of colon cancers, and the silencing of this gene is a common and early event in human colon neoplasia. We expressed this protein in Xenopus laevis oocytes and have found that it transports small monocarboxylic acids. The electrogenic activity of the cotransporter, which we have named SMCT (sodium monocarboxylate transporter), was dependent on external Na(+) and was compatible with a 3 : 1 stoichiometry between Na(+) and monocarboxylates. A portion of the SMCT-mediated current was also Cl(-) dependent, but Cl(-) was not cotransported. SMCT transports a variety of monocarboxylates (similar to unrelated monocarboxylate transport proteins) and most transported monocarboxylates demonstrated K(m) values near 100 microm, apart from acetate and d-lactate, for which the protein showed less affinity. SMCT was strongly inhibited by 1 mm probenecid or ibuprofen. In the absence of external substrate, a Na(+)-independent leak current was also observed to pass through SMCT. SMCT activity was strongly inhibited after prolonged exposure to high external concentrations of monocarboxylates. The transport of monocarboxylates in anionic form was confirmed by the observation of a concomitant alkalinization of the cytosol. SMCT, being expressed in colon and kidney, represents a novel means by which Na(+), short-chain fatty acids and other monocarboxylates are transported in these tissues. The significance of a Na(+)-monocarboxylate transporter to colon cancer presumably stems from the transport of butyrate, which is well known for having anti-proliferative and apoptosis-inducing activity in colon epithelial cells.
Coady
Michael J
MJ
Groupe d'etude des protéines membranaires, Pavillon Paul-G-Desmarais, Université de Montréal, QC, Canada.
Chang
Min-Hwang
MH
Charron
Francois M
FM
Plata
Consuelo
C
Wallendorff
Bernadette
B
Sah
Jerome Frank
JF
Markowitz
Sanford D
SD
Romero
Michael F
MF
Lapointe
Jean-Yves
JY
D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005232:Fatty Acids, Volatile / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007052:Ibuprofen / Q000494:pharmacology; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008839:Microelectrodes; D027501:Monocarboxylic Acid Transporters; D009865:Oocytes; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012964:Sodium / Q000378:metabolism; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics; D014982:Xenopus laevis
D002264:Carboxylic Acids; D027682:Cation Transport Proteins; D016861:Cyclooxygenase Inhibitors; D005232:Fatty Acids, Volatile; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; C476760:SLC5A8 protein, human; D027981:Symporters; D019344:Lactic Acid; D012964:Sodium; D007052:Ibuprofen