The HIF-2alpha dependent induction of PAP and adenosine synthesis regulates glioblastoma stem cell function through the A2B adenosine receptor

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• 作者：Tian-zhu Liu^a ; ¹ ; Xin Wang^a ; ¹ ; Yi-feng Bai^b ; Hong-zhan Liao^a ; Sheng-cong Qiu^a ; Ye-qing Yang^c ; Xiao-hui Yan^d ; Jian Chen^a ; Hong-bo Guo^a ; ^{guohongbo911@126.com" class="auth_mail} ; ^{hongbo-guo@tom.com" class="auth_mail} ; Shi-zhong Zhang^a ; ^{shizhong-zhang@tom.com" class="auth_mail}
• 关键词：PAP ; prostatic acid phosphatase ; HIF1伪/2伪 ; hypoxia-inducible factors 1伪/2伪 ; GSCs ; glioblastoma stem cells ; NSCs ; neural stem cells ; SCM ; tumor stem cell propagating medium ; MAPKs ; mitogen-activated protein kinases ; JNK ; c-Jun N-terminal kinase ; Akt/PKB ; protein kinase B ; siRNA ; small inhibitory double-stranded RNA oligonucleotides ; RT-qPCR ; real-time quantitative polymerase chain reaction
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：April, 2014
• 年：2014
• 卷：49
• 期：Complete
• 页码：8-16
• 全文大小：3645 K

文摘

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 HIF2伪 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 HIF2伪. 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 HIF2伪-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.