Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells

被引:4
|
作者
Okumura, Manabu [1 ,2 ]
Iwakiri, Tomomi [1 ]
Yoshikawa, Naoki [1 ]
Nagatomo, Takao [1 ]
Ayabe, Takanori [2 ,3 ]
Tsuneyoshi, Isao [2 ,4 ]
Ikeda, Ryuji [1 ]
机构
[1] Univ Miyazaki, Fac Med, Dept Pharm, Miyazaki 8891692, Japan
[2] Miyazaki Univ Hosp, Dept Patient Safety Management, Miyazaki 8891692, Japan
[3] Univ Miyazaki, Fac Med, Dept Surg, Div Thorac & Breast Surg, Miyazaki 8891692, Japan
[4] Univ Miyazaki, Fac Med, Dept Anesthesiol & Intens Care, Miyazaki 8891692, Japan
关键词
hepatocyte growth factor; HGF; 5-FU; UPP1; c-Met; erlotinib; RECEPTOR TYROSINE KINASE; C-MET; URIDINE PHOSPHORYLASE; OVEREXPRESSION; AMPLIFICATION; BINDING; CANCER; RILOTUMUMAB; SUPPRESSES; ACTIVATION;
D O I
10.3390/ijms23169108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页数:19
相关论文
共 50 条
  • [1] Hepatocyte growth factor suppresses the antineoplastic effect of CPT-11 by increasing the expression of CES2 and UGT1A1 in HepG2 cells
    Okumura, Manabu
    Iwakiri, Tomomi
    Takagi, Akinori
    Nagata, Masashi
    Hirabara, Yasutoshi
    Kawano, Yohei
    Arimori, Kazuhiko
    JOURNAL OF PHARMACOLOGICAL SCIENCES, 2011, 115 : 103P - 103P
  • [2] Activation of LDL receptor gene expression in HepG2 cells by hepatocyte growth factor
    Pak, YK
    Kanuck, MP
    Berrios, D
    Briggs, MR
    Cooper, AD
    Ellsworth, JL
    JOURNAL OF LIPID RESEARCH, 1996, 37 (05) : 985 - 998
  • [3] Effects of Shikoni, 5-fluorouracil and cisplatin on APRIL expression in hepatocellular carcinoma HepG2 cells
    Guo, Y. W.
    Zheng, F. P.
    Li, Y. W.
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 2009, 24 : A158 - A158
  • [4] MicroRNA-302a enhances 5-fluorouracil sensitivity in HepG2 cells by increasing AKT/ULK1-dependent autophagy-mediated apoptosis
    He, Qiong
    Li, Li
    ONCOLOGIE, 2024, 26 (02) : 211 - 220
  • [5] Inhibition of Orai1-mediated Ca2+ entry enhances chemosensitivity of HepG2 hepatocarcinoma cells to 5-fluorouracil
    Tang, Bao-Dong
    Xia, Xin
    Lv, Xiao-Fei
    Yu, Bei-Xin
    Yuan, Jia-Ni
    Mai, Xiao-Yi
    Shang, Jin-Yan
    Zhou, Jia-Guo
    Liang, Si-Jia
    Pang, Rui-Ping
    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2017, 21 (05) : 904 - 915
  • [6] Involvement of hepatocyte growth factor in increased integrin expression on HepG2 cells triggered by adhesion to endothelial cells
    N Kawakami-Kimura
    T Narita
    K Ohmori
    T Yoneda
    K Matsumoto
    T Nakamura
    R Kannagi
    British Journal of Cancer, 1997, 75 : 47 - 53
  • [7] Involvement of hepatocyte growth factor in increased integrin expression on HepG2 cells triggered by adhesion to endothelial cells
    KawakamiKimura, N
    Narita, T
    Ohmori, K
    Yoneda, T
    Matsumoto, K
    Nakamura, T
    Kannagi, R
    BRITISH JOURNAL OF CANCER, 1997, 75 (01) : 47 - 53
  • [8] Aluminum chloride causes 5-fluorouracil resistance in hepatocellular carcinoma HepG2 cells
    Li, Mengling
    Cui, Zheng-guo
    Zakki, Shahbaz Ahmad
    Feng, Qianwen
    Sun, Lu
    Feril, Loreto B., Jr.
    Inadera, Hidekuni
    JOURNAL OF CELLULAR PHYSIOLOGY, 2019, 234 (11) : 20249 - 20265
  • [9] Hepatocyte growth factor induces VEGF release from HepG2 cells
    Granot, E
    Boros, A
    Tarcsafalvi, A
    Boros, P
    Miller, CM
    HEPATOLOGY, 1998, 28 (04) : 253A - 253A
  • [10] BcI-XL Small Interfering RNA Enhances Sensitivity of Hepg2 Hepatocellular Carcinoma Cells to 5-Fluorouracil and Hydroxycamptothecin
    Xiao-Yong LEI* Miao ZHONG Lan-Fang FENG Bing-Yang ZHU Sheng-Song TANG Duan-Fang LIAO Institute of Pharmacy and Pharmacology
    Acta Biochimica et Biophysica Sinica, 2006, (10) : 704 - 710