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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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 |
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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 |
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