Oncostatin M upregulates HIF-1α in breast tumor associated macrophages independent of intracellular oxygen concentration

    loading  Checking for direct PDF access through Ovid


Aims:HIF is an important transcription-regulator for adaptation to cellular stress in cells of myeloid origin. Classically, expression and activity of HIF1-α is regulated by oxygen-concentration within cell. However, there exists an alternative regulatory mechanism affecting HIF1-α levels independent of oxygen concentration particularly in inflammatory cells like macrophages. Here we report the mechanism of HIF1-α upregulation in TAMs by Oncostatin-M (OSM) independent of cellular oxygen concentration.Main methods:THP-1 derived macrophages were treated with OSM. HIF1-α levels and interaction with pVHL were evaluated via immunoblot-analysis and Co-immunoprecipitation. Translocation of HIF1-α to nucleus was visualized using confocal-microscopy. Fold change in mRNA levels of ARG-1 and COX-2 was analyzed using RT-PCR.Key findings:Current study demonstrates that OSM treatment to TAMs led to an increased expression of HIF1-α under normoxic conditions via activation of mTORC2. This HIF1-α upregulation was dependent on both de novo synthesis of HIF1-α and its enhanced stability due to disruption of its binding to pVHL. Furthermore, we evaluated that OSM not only enhances the expression of HIF1-α but also increases its localization to nucleus where it acts as a transcription factor regulating expression of genes like ARG-1 and COX-2.Significance:Inflammation is a critical hallmark of cancer as tumor microenvironment is largely infiltrated with macrophages. These tumor associated macrophages (TAMs) display a M2 skewed phenotype. Many target genes of TAMs are HIF1-α responsive. These TAMs are involved in tumor progression, metastasis and angiogenesis. Targeting of HIF1-α/OSM can lead to devising of better therapeutic strategy against cancer.Highlights:OncostatinM (OSM) increases expression of HIF-1α under normoxic conditions in a dose and time dependent manner in TAMs.This OSM mediated HIF-1α increase is via activation of mTORC2.OSM mediated HIF-1α upregulation was dependent on both de novo synthesis as well as enhanced stability of HIF-1α.OSM increases HIF-1α nuclear localization acting as a transcription factor regulating genes like ARG-1 and COX-2.

    loading  Loading Related Articles