| First Author | Joshi S | Year | 2014 |
| Journal | Mol Cancer Res | Volume | 12 |
| Issue | 10 | Pages | 1520-31 |
| PubMed ID | 25103499 | Mgi Jnum | J:216067 |
| Mgi Id | MGI:5607665 | Doi | 10.1158/1541-7786.MCR-13-0682 |
| Citation | Joshi S, et al. (2014) A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1alpha and HIF2alpha stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res 12(10):1520-31 |
| abstractText | Tumor growth, progression, and response to the hypoxic tumor microenvironment 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-PI3K 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. |
