Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Okumura, Manabu, Iwakiri, Tomomi, Yoshikawa, Naoki, Nagatomo, Takao, Ayabe, Takanori, Tsuneyoshi, Isao, Ikeda, Ryuji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409026/
https://www.ncbi.nlm.nih.gov/pubmed/36012373
http://dx.doi.org/10.3390/ijms23169108
_version_ 1784774748677341184
author Okumura, Manabu
Iwakiri, Tomomi
Yoshikawa, Naoki
Nagatomo, Takao
Ayabe, Takanori
Tsuneyoshi, Isao
Ikeda, Ryuji
author_facet Okumura, Manabu
Iwakiri, Tomomi
Yoshikawa, Naoki
Nagatomo, Takao
Ayabe, Takanori
Tsuneyoshi, Isao
Ikeda, Ryuji
author_sort Okumura, Manabu
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9409026
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-94090262022-08-26 Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells Okumura, Manabu Iwakiri, Tomomi Yoshikawa, Naoki Nagatomo, Takao Ayabe, Takanori Tsuneyoshi, Isao Ikeda, Ryuji Int J Mol Sci Article 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. MDPI 2022-08-14 /pmc/articles/PMC9409026/ /pubmed/36012373 http://dx.doi.org/10.3390/ijms23169108 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Okumura, Manabu
Iwakiri, Tomomi
Yoshikawa, Naoki
Nagatomo, Takao
Ayabe, Takanori
Tsuneyoshi, Isao
Ikeda, Ryuji
Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells
title Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells
title_full Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells
title_fullStr Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells
title_full_unstemmed Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells
title_short Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells
title_sort hepatocyte growth factor enhances antineoplastic effect of 5-fluorouracil by increasing upp1 expression in hepg2 cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409026/
https://www.ncbi.nlm.nih.gov/pubmed/36012373
http://dx.doi.org/10.3390/ijms23169108
work_keys_str_mv AT okumuramanabu hepatocytegrowthfactorenhancesantineoplasticeffectof5fluorouracilbyincreasingupp1expressioninhepg2cells
AT iwakiritomomi hepatocytegrowthfactorenhancesantineoplasticeffectof5fluorouracilbyincreasingupp1expressioninhepg2cells
AT yoshikawanaoki hepatocytegrowthfactorenhancesantineoplasticeffectof5fluorouracilbyincreasingupp1expressioninhepg2cells
AT nagatomotakao hepatocytegrowthfactorenhancesantineoplasticeffectof5fluorouracilbyincreasingupp1expressioninhepg2cells
AT ayabetakanori hepatocytegrowthfactorenhancesantineoplasticeffectof5fluorouracilbyincreasingupp1expressioninhepg2cells
AT tsuneyoshiisao hepatocytegrowthfactorenhancesantineoplasticeffectof5fluorouracilbyincreasingupp1expressioninhepg2cells
AT ikedaryuji hepatocytegrowthfactorenhancesantineoplasticeffectof5fluorouracilbyincreasingupp1expressioninhepg2cells