科研之友
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摘要
Activation of peroxisome proliferator-activated receptor alpha (PPAR alpha) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPAR alpha activation on the hypoxia-inducible factor-1 alpha (HIF-1 alpha) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1 alpha expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPAR alpha agonists, but not a PPAR gamma agonist, prior to hypoxia diminished hypoxia-induced HIF-1 alpha expression and activity, and addition of a PPAR alpha antagonist attenuated the suppression of HIF-1 alpha signaling. Activation of PPAR alpha attenuated hypoxia-induced HA-tagged HIF-1 alpha protein expression without affecting the HA-tagged HIF-1 alpha mutant protein level, indicating that PPAR alpha activation promotes HIF-1 alpha degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPAR alpha-mediated suppression of HIF-1 alpha expression under hypoxia. Using the co-immunoprecipitation technique, we found that activation of PPAR alpha enhances the binding of HIF-1 alpha to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1 alpha degradation through the ubiquitin-proteasome pathway. Following PPAR alpha mediated suppression of HIF-1 alpha signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPAR alpha suppresses hypoxia-induced HIF-1 alpha signaling in cancer cells, providing novel insight into the anticancer properties of PPAR alpha agonists.
