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.
Subject(s)
Adenosine/biosynthesis , Basic Helix-Loop-Helix Transcription Factors/metabolism , Neoplastic Stem Cells/metabolism , Protein Tyrosine Phosphatases/metabolism , Receptor, Adenosine A2B/metabolism , Acid Phosphatase , Adenosine A2 Receptor Antagonists/pharmacology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , 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 , Humans , Male , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Phosphorylation , Protein Tyrosine Phosphatases/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Rats , Rats, Nude , Receptor, Adenosine A2B/genetics , Tumor Cells, Cultured , Xanthines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Tenascin-R (TN-R) is a neural specific protein and an important molecule involved in inhibition of axonal regeneration after spinal cord injury (SCI). Here we report on rabbit-derived TN-R polyclonal antibody, which acts as a TN-R antagonist with high titer and high specificity, promoted neurite outgrowth and sprouting of rat cortical neurons cultured on the inhibitory TN-R substrate in vitro. When locally administered into the lesion sites of rats received spinal cord dorsal hemisection, these TN-R antibodies could significantly decrease RhoA activation and improve functional recovery from corticospinal tract (CST) transection. Thus, passive immunotherapy with specific TN-R antagonist may represent a promising repair strategy following acute SCI.
