Hypoxia modulation of peroxisome proliferator‐activated receptors (PPARs) in human glioblastoma stem cells. Implications for therapy

Abstract

Gliobastoma (GB), the most common adult brain tumor, infiltrates normal brain area rendering impossible the complete surgical resection, resulting in a poor median survival (14-15 months), despite the aggressive multimodality treatments post-surgery, such as radiation and chemo-therapy. GB is characterized by hypoxic and necrotic regions due to a poorly organized tumor vascularization, leading to inadequate blood supply and consequently to hypoxic and necrotic areas. We have previously shown that, under hypoxia GB primary cells increased the expression of stemness markers as well as the expression of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and also the crucial role played by PPARs in mouse neural stem cells maintenance and differentiation. Due to the importance of lipid signaling in cell proliferation and differentiation, in this work, we analyzed the expression of PPARs in GB neurospheres both in normoxic and hypoxic conditions. The results obtained suggest a differential regulation of the three PPARs by hypoxia, thus indicating a possible therapeutic strategy to counteract GB recurrencies.

Peroxisome Proliferator Activated Receptor-α/Hypoxia Inducible Factor-1α Interplay Sustains Carbonic Anhydrase IX and Apoliprotein E Expression in Breast Cancer Stem Cells

“…We previously demonstrated that HIF1α is a TNFα target [12]. Moreover, literature data report that HIF1α is a potential PPARα target [33]. Here, we observed that exposure of MCF7-MS and MCF10-MS to the TAF supernatant elicited HIF1α transcriptional activity (Figure 2C) and mRNA expression (+65%, p <0.05, in MCF10-MS; +76%, p <0.01, in MCF7-MS, Figure S2A).…”

“…Noteworthy, PPARγ plays a significant inhibitory role on the inflammatory process [30]–[31], while PPARα exerts pro-inflammatory activity [32]. Interestingly, the expression of PPARα increases, while that of PPARγ decreases in neural stem cells exposed to hypoxia [33]. In this study, MS from normal (N-MS) and tumor (T-MS) tissues, as well as from tumorigenic MCF7 (MCF7-MS) and non tumorigenic (MCF10-MS) human breast cell lines, were exposed to the supernatant of normal mammary gland and breast tumor associated fibroblasts.…”

Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia

“…However, whether this HIF-1α–PPAR pathway occurs in cancer cells remains unclear ( Figure 2 , route 16). In cancer, PPARα is upregulated at the transcriptional level in response to hypoxia in GBM cells [ 109 , 110 ]. This PPARα activation is associated with increased HIF-1α expression, number of peroxisomes, and LD levels [ 109 , 110 ].…”

“…In cancer, PPARα is upregulated at the transcriptional level in response to hypoxia in GBM cells [ 109 , 110 ]. This PPARα activation is associated with increased HIF-1α expression, number of peroxisomes, and LD levels [ 109 , 110 ]. The lipid components of LDs, including TAG and cholesterols, are increased in GBM cells in response to hypoxia [ 109 , 110 ].…”

Inhibitors of Growth 1b Suppresses Peroxisome Proliferator-Activated Receptor-β/δ Expression Through Downregulation of Hypoxia-Inducible Factor 1α in Osteoblast Differentiation

“…PPAR activity is involved in osteoblastic differentiation (Takano et al, 2012) and hypoxia modulation of HIF1a and PPARs in human glioblastoma stems cells (Galzio et al, 2012). Evidence has also suggested that ING1b negatively regulates HIF1a protein levels in adipose-derived stromal cells in a SUMOylation-dependent mechanism (Bigot et al, 2015).…”