Tumor growth, progression and response to the hypoxic tumor microenvironment (TME) involve the action of hypoxia inducible transcription factors, HIF1 and HIF2. HIF is a heterodimeric transcription factor containing an inducible HIFalpha subunit and a constitutively expressed HIFbeta subunit. The signaling pathways operational in macrophages regulating hypoxia induced HIFalpha stabilization remain the subject of intense investigation. Here it was discovered that the PTEN/PI3K/AKT signaling axis controls hypoxia induced HIF1alpha (HIF1A) and HIF2alpha (EPAS1) stability in macrophages. Using genetic mouse models and pan-PI3 kinase as well as isoform specific inhibitors, inhibition of the PI3K/AKT pathway blocked the accumulation of HIFalpha protein and its primary transcriptional target VEGF in response to hypoxia. Moreover, blocking the PI3K/AKT signaling axis promoted the hypoxic degradation of HIFalpha via the 26S proteasome. Mechanistically, a macrophage dominant PI3K isoform (p110gamma) directed tumor growth, angiogenesis, metastasis and the HIFalpha/VEGF axis. Moreover, a pan-PI3K inhibitor (SF1126) blocked tumor-induced angiogenesis and inhibited VEGF and other proangiogenic factors secreted by macrophages. These data define a novel molecular mechanism by which PTEN/PI3K/AKT regulates the proteasome dependent stability of HIFalpha under hypoxic conditions, a signaling pathway in macrophages that controls tumor-induced angiogenesis and metastasis. Implications: This study indicates that PI3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression.
- Received January 21, 2014.
- Revision received July 21, 2014.
- Accepted July 27, 2014.
- Copyright © 2014, American Association for Cancer Research.