title: The HIF-2alpha dependent induction of PAP and adenosine synthesis regulates glioblastoma stem cell function through the A2B adenosine receptor.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Rebuild and Rehabilitation of Guangdong, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Tian-zhu
authors.initials: TZ
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Rebuild and Rehabilitation of Guangdong, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yi-feng
authors.initials: YF
authors.lastname: Bai
authors.affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Rebuild and Rehabilitation of Guangdong, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Hong-zhan
authors.initials: HZ
authors.lastname: Liao
authors.affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Rebuild and Rehabilitation of Guangdong, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Sheng-cong
authors.initials: SC
authors.lastname: Qiu
authors.affiliation: Department of Oncology and Hematology, Central Hospital, Shaoyang, China.
authors.forename: Ye-qing
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Clinical Research Centre, Nanfang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Rebuild and Rehabilitation of Guangdong, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Rebuild and Rehabilitation of Guangdong, Zhujiang Hospital of Southern Medical University, Guangzhou, China. Electronic address: guohongbo911@126.com.
authors.forename: Hong-bo
authors.initials: HB
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Rebuild and Rehabilitation of Guangdong, Zhujiang Hospital of Southern Medical University, Guangzhou, China. Electronic address: shizhong-zhang@tom.com.
authors.forename: Shi-zhong
authors.initials: SZ
authors.lastname: Zhang
mesh_terms: D000135:Acid Phosphatase; D000241:Adenosine / Q000096:biosynthesis*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011923:Rats, Nude; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000135:Acid Phosphatase; D000241:Adenosine; D058917:Adenosine A2 Receptor Antagonists; D051792:Basic Helix-Loop-Helix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D017027:Protein Tyrosine Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D000099162:Endothelial PAS Domain-Containing Protein 1; C518874:1-propyl-8-(4-sulfophenyl)xanthine; C428439:prostatic acid phosphatase
keywords: A2B receptors; Adenosine; Glioblastoma stem cells; Hypoxia; Prostatic acid phosphatase