PT  - JOURNAL ARTICLE
AU  - Stefania Merighi
AU  - Annalisa Benini
AU  - Prisco Mirandola
AU  - Stefania Gessi
AU  - Katia Varani
AU  - Edward Leung
AU  - Stephen Maclennan
AU  - Pier Giovanni Baraldi
AU  - Pier Andrea Borea
TI  - Hypoxia Inhibits Paclitaxel-Induced Apoptosis through Adenosine-Mediated Phosphorylation of Bad in Glioblastoma Cells
AID  - 10.1124/mol.106.031849
DP  - 2007 Jul 01
TA  - Molecular Pharmacology
PG  - 162--172
VI  - 72
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/72/1/162.short
4100  - http://molpharm.aspetjournals.org/content/72/1/162.full
SO  - Mol Pharmacol2007 Jul 01; 72
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics