Apolipoprotein A-I mimetic peptides inhibit expression and activity of hypoxia-inducible factor-1? in human ovarian cancer cell lines and a mouse ovarian cancer model.

ABSTRACT: Our previous results demonstrated that the apolipoprotein A-I (apoA-I) mimetic peptides L-4F and L-5F inhibit vascular endothelial growth factor production and tumor angiogenesis. The present study was designed to test whether apoA-I mimetic peptides inhibit the expression and activity of hypoxia-inducible factor-1? (HIF-1?), which plays a critical role in the production of angiogenic factors and angiogenesis. Immunohistochemistry staining was used to examine the expression of HIF-1? in tumor tissues. Immunoblotting, real-time polymerase chain reaction, immunofluorescence, and luciferase activity assays were used to determine the expression and activity of HIF-1? in human ovarian cancer cell lines. Immunohistochemistry staining demonstrated that L-4F treatment dramatically decreased HIF-1? expression in mouse ovarian tumor tissues. L-4F inhibited the expression and activity of HIF-1? induced by low oxygen concentration, cobalt chloride (CoCl(2), a hypoxia-mimic compound), lysophosphatidic acid, and insulin in two human ovarian cancer cell lines, OV2008 and CAOV-3. L-4F had no effect on the insulin-induced phosphorylation of Akt, but inhibited the activation of extracellular signal-regulated kinase and p70s6 kinase, leading to the inhibition of HIF-1? synthesis. Pretreatment with L-4F dramatically accelerated the proteasome-dependent protein degradation of HIF-1? in both insulin- and CoCl(2)-treated cells. The inhibitory effect of L-4F on HIF-1? expression is in part mediated by the reactive oxygen species-scavenging effect of L-4F. ApoA-I mimetic peptides inhibit the expression and activity of HIF-1? in both in vivo and in vitro models, suggesting the inhibition of HIF-1? may be a critical mechanism responsible for the suppression of tumor progression by apoA-I mimetic peptides.

SUBMITTER: Gao F 

PROVIDER: S-EPMC3400800 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other