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Hypoxia Inhibits Paclitaxel-Induced Apoptosis through Adenosine-Mediated Phosphorylation of Bad in Glioblastoma Cells

Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, Ferrara, Italy (S.M., A.B., S.G., K.V., P.A.B.); Department of Human Anatomy, Pharmacology, and Forensic Medicine, Human Anatomy Section, University of Parma, Parma, Italy (P.M.); King Pharmaceuticals R&D, Cary, North Carolina (S.M.L., E.L.); Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy (P.G.B.); and Interdisciplinary Center for the Study of Inflammation, Ferrara, Italy (P.A.B.)

Solid tumors contain hypoxic cells that are resistant to radiotherapy and chemotherapy. The resistance in glioblastoma has been linked to the expression of antiapoptotic Bcl-2 family members. In this study, we found that in human glioblastoma cells hypoxia induces the phosphorylation of the Bcl-2 family protein Bad, thus protecting hypoxic cells from paclitaxel-induced apoptosis. Akt activation is required for the hypoxia-induced protection. In contrast, the extracellular signal-regulated kinase 1/2 activities have only a partial effect, being able to modulate Bad phosphorylation but not paclitaxel-induced apoptosis in hypoxia. We also demonstrated that the degradation of adenosine with adenosine deaminase, the knockdown of A₃ adenosine receptor expression by gene silencing, and the blockade of this receptor through A₃ receptor antagonists blocked the hypoxia-induced phosphorylation of Bad and the prolonged cell survival after treatment with paclitaxel in hypoxia. Thus, the adenosinergic signaling may be an essential component in the hypoxia survival pathway. These results suggest that hypoxia-induced chemoresistance of human glioblastoma cells may occur in a novel mechanism involving activation of adenosine-A₃ receptor-Akt pathway, which mediates Bad inactivation and favors cell survival.

Address correspondence to: Dr. Pier Andrea Borea, Department of Clinical and Experimental Medicine, Pharmacology Section, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. E-mail: bpa{at}unife.it