RT Journal Article
SR Electronic
T1 Apolipoprotein A-I Mimetic Peptides Inhibit Expression and Activity of Hypoxia-Inducible Factor-1α in Human Ovarian Cancer Cell Lines and a Mouse Ovarian Cancer Model
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 255
OP 262
DO 10.1124/jpet.112.191544
VO 342
IS 2
A1 Gao, Feng
A1 Chattopadhyay, Arnab
A1 Navab, Mohamad
A1 Grijalva, Victor
A1 Su, Feng
A1 Fogelman, Alan M.
A1 Reddy, Srinivasa T.
A1 Farias-Eisner, Robin
YR 2012
UL http://jpet.aspetjournals.org/content/342/2/255.abstract
AB 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-1α (HIF-1α), which plays a critical role in the production of angiogenic factors and angiogenesis. Immunohistochemistry staining was used to examine the expression of HIF-1α in tumor tissues. Immunoblotting, real-time polymerase chain reaction, immunofluorescence, and luciferase activity assays were used to determine the expression and activity of HIF-1α in human ovarian cancer cell lines. Immunohistochemistry staining demonstrated that L-4F treatment dramatically decreased HIF-1α expression in mouse ovarian tumor tissues. L-4F inhibited the expression and activity of HIF-1α induced by low oxygen concentration, cobalt chloride (CoCl2, 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-1α synthesis. Pretreatment with L-4F dramatically accelerated the 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 in part mediated by the reactive oxygen species-scavenging effect of L-4F. ApoA-I mimetic peptides inhibit the expression and activity of HIF-1α in both in vivo and in vitro models, suggesting the inhibition of HIF-1α may be a critical mechanism responsible for the suppression of tumor progression by apoA-I mimetic peptides.