title: NK4 gene expression enhances 5-fluorouracil-induced apoptosis of murine colon cancer cells.
abstract: BACKGROUND
  The hepatocyte growth factor (HGF)-Met pathway plays a role in progression to malignant characteristics in tumors, including that of resistance to anticancer drugs. The purpose of this study was to elucidate the possibility of the combination therapy of NK4, a competitive antagonist for HGF.
  
  
  METHODS
  We established a genetically modified murine colon cancer cell, CT26, to produce abundant NK4 (CT26/NK4). Cell proliferation, apoptosis, cell cycle, intracellular signaling, and 5-fluorouracil (5-FU) metabolism of this cell line were examined.
  
  
  RESULTS
  There was no difference in thymidylate synthase mRNA level between mock-transfected control CT26 cells and CT26/NK4 cells, suggesting that NK4 expression does not change 5-FU metabolism. NK4 gene expression enhanced 5-FU-induced caspase-3 and -7 activation of CT26. Cell cycle analysis showed that NK4 gene expression and 5-FU treatment caused an increase in the proportion of sub-G(1) cells. On 5-FU treatment, phosphorylation of Akt and Erk1/2 was suppressed in CT26/NK4 less than in mock-transfected cells. 5-FU showed a stronger cytotoxic activity towards CT26/NK4 cells than control CT26 cells.
  
  
  CONCLUSIONS
  5-FU exerts an additional effect on apoptosis of NK4-expressing CT26 cells by down-regulating intracellular signaling of the HGF/c-Met pathway.
authors: Department of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. taiyoh@koto.kpu-m.ac.jp
authors: Hiroaki
authors: H
authors: Taiyoh
authors: Takeshi
authors: T
authors: Kubota
authors: Hitoshi
authors: H
authors: Fujiwara
authors: Atsushi
authors: A
authors: Matsumura
authors: Yasutoshi
authors: Y
authors: Murayama
authors: Kazuma
authors: K
authors: Okamoto
authors: Daisuke
authors: D
authors: Ichikawa
authors: Toshiya
authors: T
authors: Ochiai
authors: Takahiro
authors: T
authors: Nakamura
authors: Kunio
authors: K
authors: Matsumoto
authors: Toshikazu
authors: T
authors: Nakamura
authors: Eigo
authors: E
authors: Otsuji
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D006224:Cricetinae; D003412:Cricetulus; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D043823:Taxoids; D000077143:Docetaxel; D017228:Hepatocyte Growth Factor; D013940:Thymidylate Synthase; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin; D005472:Fluorouracil