2',4',6'-Tris(methoxymethoxy) chalcone attenuates hepatic stellate cell proliferation by a heme oxygenase-dependent pathway.
Proliferation of hepatic stellate cells (HSCs) is central for the development of fibrosis during liver injury. We have shown previously that butein (3,4,2',4'-tetrahydroxychalcone) suppresses myofibroblastic differentiation of rat HSCs. Our aim in this study was to determine whether a new synthetic chalcone derivative, 2',4',6'-tris(methoxymethoxy) chalcone (TMMC) inhibits HSC proliferation induced by serum- or platelet-derived growth factor (PDGF). TMMC significantly inhibited growth factor-induced HSC proliferation. The inhibition of PDGF-induced proliferation by TMMC was associated with the phosphatidylinositol 3-kinase-Akt-p70(S6K) pathways. TMMC induced the expression of heme oxygenase 1 (HO-1) in HSCs. Using the chemical inhibitor tin protoporphyrin, we also found that the inhibitory action of TMMC on PDGF-induced proliferation is mediated by HO-1. Glutathione (GSH) depletion produced by TMMC activated extracellular signal-regulated kinase (ERK), which led to c-Fos expression and transactivation of activator protein 1 (AP-1) and HO-1 gene expression in the HSCs. These results demonstrate that TMMC preferentially activates ERK and that this activation leads to the transcriptional activation of AP-1 and consequently to HO-1 expression. HO-1 expression might be responsible for the antiproliferative effect of TMMC on HSCs.
Lee
Sung Hee
SH
College of Pharmacy, Medicinal Resources Research Institute, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
Seo
Geom Seog
GS
Kim
Hak Sung
HS
Woo
Sun Wook
SW
Ko
Geonil
G
Sohn
Dong Hwan
DH
D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
C510589:2',4',6'-tris(methoxymethoxy) chalcone; D047188:Chalcones; D016895:Culture Media, Serum-Free; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione