The HIF-2alpha dependent induction of PAP and adenosine synthesis regulates glioblastoma stem cell function through the A2B adenosine receptor
| Autor: | Hongzhan Liao, Tianzhu Liu, Hongbo Guo, Yifeng Bai, Jian Chen, Shizhong Zhang, Xiaohui Yan, Xin Wang, Ye-qing Yang, Shengcong Qiu |
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| Rok vydání: | 2014 |
| Předmět: |
Male
endocrine system Adenosine Acid Phosphatase Blotting Western Tumor initiation Biology Receptor Adenosine A2B Biochemistry Rats Nude Cell Line Tumor Basic Helix-Loop-Helix Transcription Factors Tumor Cells Cultured medicine Animals Humans Phosphorylation Extracellular Signal-Regulated MAP Kinases Receptor Protein kinase B Cells Cultured Cell Proliferation fungi Cell Biology Xenograft Model Antitumor Assays Adenosine receptor Molecular biology Cell Hypoxia Neural stem cell Adenosine A2 Receptor Antagonists Rats Xanthines Neoplastic Stem Cells Cancer research Female RNA Interference Protein Tyrosine Phosphatases Stem cell Glioblastoma Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | The International Journal of Biochemistry & Cell Biology. 49:8-16 |
| ISSN: | 1357-2725 |
| Popis: | Glioblastomas are lethal tumors characterized by malignant proliferation and recurrence promoted partly by glioblastoma stem cells (GSCs). GSCs are known to be regulated by hypoxia, but the mechanisms involved in this regulation are not fully understood. We now demonstrate that hypoxia-inducible factor HIF2α and prostatic acid phosphatase (PAP) are preferentially expressed in hypoxic GSCs in comparison with non-stem tumor cells and normal neural stem cells and that PAP is regulated by HIF2α. Targeting PAP in hypoxic GSCs inhibits self-renewal and proliferation in vitro and attenuates tumor initiation potential of GSCs in vivo. Using specific adenosine receptor antagonists, we further find that the pro-proliferative role of PAP is stemmed from stimulated A2B adenosine receptors. Moreover, selective blockage of A2B receptor or knockdown of PAP or A2B on hypoxic GSCs results in significant reduction of phosphorylation of Akt and Erk-1/2. Our results demonstrate that PAP may play a pro-proliferative role in hypoxic GSCs with a HIF2α-induction pattern, which may be ascribed to stimulated A2B receptors and activated Akt and Erk-1/2 pathways. Therefore, we propose that these identified molecular regulators of GSCs in the hypoxic niche might represent promising targets for antiglioblastoma therapies. |
| Databáze: | OpenAIRE |
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