Previous work from Farias-Eisner's group has demonstrated in ovarian cancer that serum apolipoprotein A-I (apoA-I) levels are significantly decreased, that overexpression of apoA-I inhibits tumor growth and improves survival in a mouse model, and that apoA-I mimetic peptides inhibited tumor growth similar to apoA-I overexpression. Gao et al. demonstrate that apoA-I mimetic peptide L-4F treatment dramatically decreased hypoxia-inducible factor (HIF-1α) expression in mouse ovarian tumor tissues. L-4F inhibited expression and activity of HIF-1α induced by low oxygen concentration, cobalt chloride (CoCl2, a hypoxia-mimic compound), lysophosphatidic acid, and insulin in human ovarian cancer cell lines. L-4F had no effect on insulin-induced phosphorylation of Akt, but inhibited activation of extracellular signal-regulated kinase and p70s6 kinase, leading to inhibition of HIF-1α synthesis. Pretreatment with L-4F dramatically accelerated proteasome-dependent protein degradation of HIF-1α in both insulin- and CoCl2-treated cells. The inhibitory effect of L-4F on HIF-1α expression is mediated in part by the reactive oxygen species-scavenging effect of L-4F. These data demonstrate that apoA-I mimetic peptides inhibit expression and activity of HIF-1α both in vivo and in cell culture and that inhibition of HIF-1α may be a critical mechanism responsible for suppression of tumor progression by apoA-I mimetic peptides.
See article at J Pharmacol Exp Ther 2012, 342:255–262.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics