Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells.
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 A(3) adenosine receptor expression by gene silencing, and the blockade of this receptor through A(3) 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-A(3) receptor-Akt pathway, which mediates Bad inactivation and favors cell survival.
Merighi
Stefania
S
Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, Ferrara, Italy.
Benini
Annalisa
A
Mirandola
Prisco
P
Gessi
Stefania
S
Varani
Katia
K
Leung
Edward
E
Maclennan
Stephen
S
Baraldi
Pier Giovanni
PG
Borea
Pier Andrea
PA
D000241:Adenosine / Q000502:physiology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D043684:Receptor, Adenosine A3 / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D043684:Receptor, Adenosine A3; D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt; D000241:Adenosine; D017239:Paclitaxel