RRC ID 74568
著者 Okumura M, Iwakiri T, Yoshikawa N, Nagatomo T, Ayabe T, Tsuneyoshi I, Ikeda R.
タイトル Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells.
ジャーナル Int J Mol Sci
Abstract Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.
巻・号 23(16)
公開日 2022-8-14
DOI 10.3390/ijms23169108
PII ijms23169108
PMID 36012373
PMC PMC9409026
MeSH Antineoplastic Agents* / pharmacology Cell Proliferation Erlotinib Hydrochloride / pharmacology Extracellular Signal-Regulated MAP Kinases / metabolism Fluorouracil / pharmacology Hep G2 Cells Hepatocyte Growth Factor* / metabolism Humans Proto-Oncogene Proteins c-met / metabolism
IF 4.556
リソース情報
ヒト・動物細胞 Hep G2(RCB1648)