Apolipoprotein A-I Mimetic Peptides Inhibit Expression and Activity of Hypoxia-Inducible Factor-1 alpha in Human Ovarian Cancer Cell Lines and a Mouse Ovarian Cancer Model

作者：Gao Feng; Chattopadhyay Arnab; Navab Mohamad; Grijalva Victor; Su Feng; Fogelman Alan M; Reddy Srinivasa T; Farias Eisner Robin^*

来源：Journal of Pharmacology and Experimental Therapeutics, 2012, 342(2): 255-262.

DOI：10.1124/jpet.112.191544

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 alpha (HIF-1 alpha), which plays a critical role in the production of angiogenic factors and angiogenesis. Immunohistochemistry staining was used to examine the expression of HIF-1 alpha in tumor tissues. Immunoblotting, real-time polymerase chain reaction, immunofluorescence, and luciferase activity as-says were used to determine the expression and activity of HIF-1 alpha in human ovarian cancer cell lines. Immunohistochemistry staining demonstrated that L-4F treatment dramatically decreased HIF-1 alpha expression in mouse ovarian tumor tissues. L-4F inhibited the expression and activity of HIF-1 alpha induced by low oxygen concentration, cobalt chloride (CoCl2, a hypoxiamimic 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 alpha synthesis. Pretreatment with L-4F dramatically accelerated the proteasome-dependent protein degradation of HIF-1 alpha in both insulinand CoCl2-treated cells. The inhibitory effect of L-4F on HIF-1 alpha 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 alpha in both in vivo and in vitro models, suggesting the inhibition of HIF-1 alpha may be a critical mechanism responsible for the suppression of tumor progression by apoA-I mimetic peptides.

• 出版日期2012-8