A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis.
Mol Cancer Res
; 12(10): 1520-31, 2014 Oct.
Article
in En
| MEDLINE
| ID: mdl-25103499
ABSTRACT
UNLABELLED 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 HIFα subunit and a constitutively expressed HIFß subunit. The signaling pathways operational in macrophages regulating hypoxia-induced HIFα stabilization remain the subject of intense investigation. Here, it was discovered that the PTEN/PI3K/AKT signaling axis controls hypoxia-induced HIF1α (HIF1A) and HIF2α (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 HIFα protein and its primary transcriptional target VEGF in response to hypoxia. Moreover, blocking the PI3K/AKT signaling axis promoted the hypoxic degradation of HIFα via the 26S proteasome. Mechanistically, a macrophage-dominant PI3K isoform (p110γ) directed tumor growth, angiogenesis, metastasis, and the HIFα/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 HIFα 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphatidylinositol 3-Kinases
/
Basic Helix-Loop-Helix Transcription Factors
/
Hypoxia-Inducible Factor 1, alpha Subunit
/
Macrophages
/
Neoplasms
/
Neovascularization, Pathologic
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Mol Cancer Res
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2014
Document type:
Article