LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers

Takaaki Abe, Michiaki Unno, Tohru Onogawa, Taro Tokui, Tohru Noriko Kondo, Rie Nakagomi, Hisanobu Adachi, Koh Fujiwara, Mitsunori Okabe, Takehiro Suzuki, Kazuo Nunoki, Eiichi Sato, Masayuki Kakyo, Toshiyuki Nishio, Junichi Sugita, Naoki Asano, Masayuki Tanemoto, Makoto Seki, Katsuhiko Ono, Yoshiaki KondoKenichi Shiiba, Masanori Suzuki, Haruo Ohtani, Tooru Shimosegawa, Kazuie Iinuma, Hiroshi Nagura, Sadayoshi Ito, Seiki Matsuno

研究成果: Article査読

291 被引用数 (Scopus)


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.

出版ステータスPublished - 2001

ASJC Scopus subject areas

  • 肝臓学
  • 消化器病学


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