LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers.
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Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma K, Nagura H, Ito S, Matsuno S
LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers.
Gastroenterology. 2001 Jun;120(7):1689-99.
- PubMed ID
- 11375950 [ View in PubMed]
- Abstract
BACKGROUND & AIMS: One approach to the development of targeted cancer chemotherapy exploits increased uptake of the agent into neoplastic cells. In this scenario, higher concentrations of the agent in cancer cells are responsible for differential killing, whereas the low concentration in normal human cells decreases side effects. The aim of this study was to isolate an organic anion transporter that is weak in normal cells, but abundantly expressed in cancer cells, to deliver the anticancer drugs to the cells. METHODS: A human liver complementary DNA (cDNA) library was screened with liver-specific transporter (LST)-1 cDNA as a probe. Northern blot analyses were performed using the isolated cDNA (termed LST-2). An LST-2-specific antibody was raised, and immunohistochemical analyses including immunoelectron microscopy were performed. Xenopus oocyte expression system was used for functional analysis. We also established a permanent cell line that consistently expresses LST-2 to examine the relationship between methotrexate uptake and sensitivity. RESULTS: The isolated cDNA, LST-2, has 79.7% of overall homology with human LST-1. LST-2 exclusively expressed in the liver under normal conditions and its immunoreactivity was highest at the basolateral membrane of the hepatocytes around the central vein. Although its weak expression in the liver, LST-2 is abundantly expressed in the gastric, colon, and pancreatic cancers. On the other hand, the LST-1 was only detected in a hepatic cell line. LST-2 transports methotrexate in a saturable and dose-dependent manner. Furthermore, introduction of the LST-2 gene into mammalian cells potentiates sensitivity to methotrexate. CONCLUSIONS: LST-2 is one of the prime candidate molecules for determining methotrexate sensitivity and may be a good target to deliver anticancer drugs to the gastrointestinal cancers.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Liothyronine Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownSubstrateDetails Liotrix Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownSubstrateDetails Methotrexate Solute carrier organic anion transporter family member 1B1 Protein Humans UnknownSubstrateDetails Methotrexate Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownSubstrateDetails Taurocholic acid Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownSubstrateDetails - Polypeptides
Name UniProt ID Solute carrier organic anion transporter family member 1B3 Q9NPD5 Details