Erythromycin and clarithromycin modulation of growth factor-induced expression of heparanase mRNA on human lung cancer cells in vitro.

Masahiro Sasaki,Masayuki Kashima,Masaaki Sano,Yosimasa Fujiwara,Noriko Izumiyama,Akiko Watanabe,Shin Fukui,Takefumi Ito,Mamoru Miura

doi:10.1080/09629350120093731

Masahiro Sasaki, Masayuki Kashima + Show 7 more

Open Access

https://doi.org/10.1080/09629350120093731

Copy DOI

Journal: Mediators of Inflammation	Publication Date: Jan 1, 2000
Citations: 17	License type: CC BY 3.0

Affiliation: Akita University

Abstract

Heparanase activity is correlated with the metastatic potential of several cancer cells and is a key enzyme in the breakdown of tissue barriers. It is also involved in the regulation of growth factor and cytokine activity. However, little is known about the factors that induce heparanase in cancer cells. We investigated the effect of three growth factors, platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF), on heparanase mRNA induction in lung cancer cells in vitro. In addition, we examined the effect of erythromycin (EM) and clarithromycin (CAM), which are 14-membered ring macrolide antibiotics that act as biological response modifiers, on the expression of heparanase mRNA induced by growth factors. PDGF, HGF and bFGF stimulated cell migration activity and enhanced the expression of heparanase mRNA in the human lung adenocarcinoma cell line A549. Via different mechanisms, EM and CAM modulate the induction by these factors of heparanase mRNA expression on A549 cells. EM also significantly suppressed A549 cell migration induced by PDGF and HGF, and CAM significantly suppressed A549cell migration induced by bFGF. The results suggest that the growth factors PDGF, HGF and bFGF are important inducers of heparanase in potentially invasive and metastatic cancer cells. The suppressive effect of heparanase mRNA expression by EM and CAM may have interestingtherapeutic applications in the prevention of metastasis.

Highlights

Cancer cell migration through the basement membranes and degradation of extracellular matrix proteins play an essential role in the various biological and pathological processes in tumor invasion and metastasis.Histological specimens from lung cancers have documented that central fibrosis and active fibroblast proliferation are among the most important prognostic factors for small bronchioalveolar carcinoma.[1,2] These same studies emphasized the importance of cancer cell-fibroblast interactions in the process of metastasis
Heparin had no inhibitory effects on heparanase mRNA expression (Fig. 3)
EM significantly suppressed A549 cell migration induced by platelet-derived growth factor (PDGF) and hepatocyte growth factor (HGF), and CAM significantly suppressed A549 cell migration induced by basic fibroblast growth factor (bFGF) (p < 0.05; Fig. 2)

Summary

Introduction

Histological specimens from lung cancers have documented that central fibrosis and active fibroblast proliferation are among the most important prognostic factors for small bronchioalveolar carcinoma.[1,2] These same studies emphasized the importance of cancer cell-fibroblast interactions in the process of metastasis. These interactions regulate growth factor and matrix metalloproteinase (MMP) production in cancer cells, which leads to the continuation of cell migration.[3,4,5]. HSPGs are thought to be involved in cell adhesion, migration, proliferation and angiogenesis.[6,7] Various classes of enzymes have been reported to play a role in the metastatic process including serine and cysteine protease, MMP and heparanase.[8,9,10,11]

Methods

Results

Conclusion