The international journal of biochemistry & cell biology, 2014-04, Vol.49, p.8-16
2014
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- Autor(en) / Beteiligte
- Titel
- The HIF-2alpha dependent induction of PAP and adenosine synthesis regulates glioblastoma stem cell function through the A2B adenosine receptor
- Ist Teil von
- The international journal of biochemistry & cell biology, 2014-04, Vol.49, p.8-16
- Ort / Verlag
- Netherlands: Elsevier Ltd
- Erscheinungsjahr
- 2014
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1357-2725eISSN: 1878-5875DOI: 10.1016/j.biocel.2014.01.007Titel-ID: cdi_proquest_miscellaneous_1730051422
- Format
- –
- Schlagworte
- A2B receptors, Acid Phosphatase, Adenosine, Adenosine - biosynthesis, Adenosine A2 Receptor Antagonists - pharmacology, Adenosines, Animals, Basic Helix-Loop-Helix Transcription Factors - genetics, Basic Helix-Loop-Helix Transcription Factors - metabolism, Blockage, Blotting, Western, Cell Hypoxia, Cell Line, Tumor, Cell Proliferation - drug effects, Cells, Cultured, Extracellular Signal-Regulated MAP Kinases - metabolism, Female, Glioblastoma - genetics, Glioblastoma - metabolism, Glioblastoma - pathology, Glioblastoma stem cells, Humans, Hypoxia, Male, Neoplastic Stem Cells - drug effects, Neoplastic Stem Cells - metabolism, Neoplastic Stem Cells - pathology, Phosphorylation, Prostatic acid phosphatase, Protein Tyrosine Phosphatases - genetics, Protein Tyrosine Phosphatases - metabolism, Proto-Oncogene Proteins c-akt - metabolism, Rats, Rats, Nude, Receptor, Adenosine A2B - genetics, Receptor, Adenosine A2B - metabolism, Receptors, Reduction, RNA Interference, Stem cells, Surgical implants, Tumor Cells, Cultured, Tumors, Xanthines - pharmacology, Xenograft Model Antitumor Assays