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.
机构:
Sun Yat Sen Univ, Affiliated Hosp 3, Dept Gastroenterol, Guangzhou 510275, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 3, Dept Gastroenterol, Guangzhou 510275, Guangdong, Peoples R China
Guo, Y. W.
Zheng, F. P.
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Sun Yat Sen Univ, Affiliated Hosp 3, Dept Gastroenterol, Guangzhou 510275, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 3, Dept Gastroenterol, Guangzhou 510275, Guangdong, Peoples R China
Zheng, F. P.
Li, Y. W.
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Sun Yat Sen Univ, Affiliated Hosp 3, Dept Gastroenterol, Guangzhou 510275, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 3, Dept Gastroenterol, Guangzhou 510275, Guangdong, Peoples R China
机构:
Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Tang, Bao-Dong
Xia, Xin
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Sun Yat Sen Univ, Affiliated Hosp 1, Dept Thorac Surg, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Xia, Xin
Lv, Xiao-Fei
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Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Cardiac & Cerebrovasc Res Ctr, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Lv, Xiao-Fei
Yu, Bei-Xin
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Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Cardiac & Cerebrovasc Res Ctr, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Yu, Bei-Xin
Yuan, Jia-Ni
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Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Cardiac & Cerebrovasc Res Ctr, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Yuan, Jia-Ni
Mai, Xiao-Yi
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Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Cardiac & Cerebrovasc Res Ctr, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Mai, Xiao-Yi
Shang, Jin-Yan
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Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Cardiac & Cerebrovasc Res Ctr, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Shang, Jin-Yan
Zhou, Jia-Guo
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Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Cardiac & Cerebrovasc Res Ctr, Guangzhou, Guangdong, Peoples R China
Sun Yat Sen Univ, Guangdong Prov Key Lab Brain Funct & Dis, Zhongshan Sch Med, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Zhou, Jia-Guo
Liang, Si-Jia
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Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Cardiac & Cerebrovasc Res Ctr, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
Liang, Si-Jia
Pang, Rui-Ping
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Sun Yat Sen Univ, Guangdong Prov Key Lab Brain Funct & Dis, Zhongshan Sch Med, Guangzhou, Guangdong, Peoples R China
Sun Yat Sen Univ, Zhongshan Sch Med, Dept Physiol, Pain Res Ctr, Guangzhou, Guangdong, Peoples R ChinaSun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China
机构:
Mt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USAMt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USA
Granot, E
Boros, A
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Mt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USAMt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USA
Boros, A
Tarcsafalvi, A
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Mt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USAMt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USA
Tarcsafalvi, A
Boros, P
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Mt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USAMt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USA
Boros, P
Miller, CM
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Mt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USAMt Sinai Med Ctr, Recanati Miller Transplantat Inst, New York, NY 10029 USA