TY - JOUR T1 - <em>NK4</em> Gene Expression Enhances 5-Fluorouracil-induced Apoptosis of Murine Colon Cancer Cells JF - Anticancer Research JO - Anticancer Res SP - 2217 LP - 2224 VL - 31 IS - 6 AU - HIROAKI TAIYOH AU - TAKESHI KUBOTA AU - HITOSHI FUJIWARA AU - ATSUSHI MATSUMURA AU - YASUTOSHI MURAYAMA AU - KAZUMA OKAMOTO AU - DAISUKE ICHIKAWA AU - TOSHIYA OCHIAI AU - TAKAHIRO NAKAMURA AU - KUNIO MATSUMOTO AU - TOSHIKAZU NAKAMURA AU - EIGO OTSUJI Y1 - 2011/06/01 UR - http://ar.iiarjournals.org/content/31/6/2217.abstract N2 - 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. Materials and 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-G1 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. Conclusion: 5-FU exerts an additional effect on apoptosis of NK4-expressing CT26 cells by down-regulating intracellular signaling of the HGF/c-Met pathway. ER -