title: Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells.
abstract: Cancer cells show constitutive upregulation of glycolysis, and the concentration of lactate thus produced correlates with prognosis. Here, we examined whether lactate concentration and lactate transporter expression are related to migration and invasion activity. We found that the expression of the monocarboxylate transporters MCT1 and MCT4, but not MCT5, in human lung cancer cell lines was significantly correlated with invasiveness. To clarify the effects of MCT1 and MCT4 expression on invasion, we performed migration and invasion assays after transfection with siRNA specific for MCT1 or MCT4. Knockdown of MCT1 or MCT4 did not influence cell migration but reduced invasion; this was also observed for knockdown of the lactate transporter-associated protein basigin. We also demonstrated that both expression and activity of MMP9 and MMP2 were not correlated with invasion activity and not regulated by MCT1, MCT4 and basigin. Furthermore, the addition of lactate did not increase migration and invasion activity, but low concentration of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), a general anion channel blocker, as well as other MCT inhibitors quercetin and simvastatin, inhibited cell invasion without influencing migration activity and the cellular expression of MCT1 and MCT4. This is the first report suggesting that lactate transporters are involved in human cancer cell invasiveness. As such, these proteins may be promising targets for the prevention of cancer invasion and metastasis.
authors.affiliation: Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan. h-izumi@med.uoeh-u.ac.jp
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.forename: Mayu
authors.initials: M
authors.lastname: Takahashi
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Oyama
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nishizawa
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
mesh_terms: D051926:Basigin / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D051926:Basigin; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human