Abstract
BackgroundLuteolin is a 3',4',5,7-tetrahydroxyflavone found in various fruits and vegetables. We have shown previously that luteolin reduces HT-29 cell growth by inducing apoptosis and cell cycle arrest. The objective of this study was to examine whether luteolin downregulates the insulin-like growth factor-I receptor (IGF-IR) signaling pathway in HT-29 cells.MethodsIn order to assess the effects of luteolin and/or IGF-I on the IGF-IR signaling pathway, cells were cultured with or without 60 μmol/L luteolin and/or 10 nmol/L IGF-I. Cell proliferation, DNA synthesis, and IGF-IR mRNA levels were evaluated by a cell viability assay, [3H]thymidine incorporation assays, and real-time polymerase chain reaction, respectively. Western blot analyses, immunoprecipitation, and in vitro kinase assays were conducted to evaluate the secretion of IGF-II, the protein expression and activation of IGF-IR, and the association of the p85 subunit of phophatidylinositol-3 kinase (PI3K) with IGF-IR, the phosphorylation of Akt and extracellular signal-regulated kinase (ERK)1/2, and cell division cycle 25c (CDC25c), and PI3K activity.ResultsLuteolin (0 - 60 μmol/L) dose-dependently reduced the IGF-II secretion of HT-29 cells. IGF-I stimulated HT-29 cell growth but did not abrogate luteolin-induced growth inhibition. Luteolin reduced the levels of the IGF-IR precursor protein and IGF-IR transcripts. Luteolin reduced the IGF-I-induced tyrosine phosphorylation of IGF-IR and the association of p85 with IGF-IR. Additionally, luteolin inhibited the activity of PI3K activity as well as the phosphorylation of Akt, ERK1/2, and CDC25c in the presence and absence of IGF-I stimulation.ConclusionsThe present results demonstrate that luteolin downregulates the activation of the PI3K/Akt and ERK1/2 pathways via a reduction in IGF-IR signaling in HT-29 cells; this may be one of the mechanisms responsible for the observed luteolin-induced apoptosis and cell cycle arrest.
Highlights
Luteolin is a 3’,4’,5,7-tetrahydroxyflavone found in various fruits and vegetables
Luteolin reduces insulin-like growth factor-II (IGF-II) secretion in HT-29 cells In the previous study, we observed that luteolin inhibited HT-29 human colon cancer cell proliferation by inducing cell cycle arrest and apoptosis [21]
In order to assess the effect of luteolin on IGFII secretion of HT-29 cells, cells were treated with 20 60 μmol/L of luteolin for 24 h and conditioned media were assayed via immunoblot analysis
Summary
Luteolin is a 3’,4’,5,7-tetrahydroxyflavone found in various fruits and vegetables. We have shown previously that luteolin reduces HT-29 cell growth by inducing apoptosis and cell cycle arrest. The objective of this study was to examine whether luteolin downregulates the insulin-like growth factor-I receptor (IGF-IR) signaling pathway in HT-29 cells. Insulin receptor substrate-1 can be recruited and phosphorylated on multiple tyrosine residues that function as docking sites for the p85 subunit of phosphatidylinositol 3-kinase (PI3K) and activate the PI3K/Akt signaling pathway (reviewed in [4,5]). The activation of these pathways induces cell cycle progression and prevents apoptosis [6,7]. We have previously reported that, in human colon cancer cells, including HT-29 cells and Caco-2 cells, IGF-II is synthesized and secreted, and an IGF-II autocrine loop stimulates the growth of these cancer cells [10,11]
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