A(2a) adenosine receptor mediates HepG2 cell apoptosis by downregulating Bcl-X(L) expression and upregulating Bid expression.
Extracellular adenosine induced apoptosis in HepG2 cells, a human hepatoma cell line, by tuning apoptosis-mediator gene transcription. The present study aimed at identifying the responsible adenosine receptor and clarifying the signaling pathway underlying adenosine-induced HepG2 cell apoptosis. Adenosine and CGS21680, an A(2a) adenosine receptor agonist, induced HepG2 cell apoptosis, and the effect was inhibited by DMPX, an A(2a) adenosine receptor antagonist, or by knocking-down A(2a) adenosine receptors. Adenosine reduced expression of Bcl-X(L) mRNA and protein but otherwise increased expression of the Bid mRNA and protein in HepG2 cells, and those effects were also prevented by knocking-down A(2a) adenosine receptors. Adenosine caused disruption of mitochondrial membrane potentials and stimulated cytochrome c efflux from the mitochondria in HepG2 cells. Adenosine activated caspases-3 and -9 in HepG2 cells, which was significantly inhibited by knocking-down A(2a) adenosine receptors. The results of the present study indicate that extracellular adenosine downregulates Bcl-X(L) expression and upregulates Bid expression, thereby disrupting mitochondrial membrane potentials to allow cytochrome c efflux from the mitochondria, and then causing activation of caspase-9 and the effector caspase-3, as mediated via A(2a) adenosine receptors.
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
Kunihiro
K
Tamura
Takeshi
T
Kanno
Yumiko
Y
Fujita
Akinobu
A
Gotoh
Takashi
T
Nakano
Tomoyuki
T
Nishizaki
D000241:Adenosine / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
D058908:Adenosine A2 Receptor Agonists; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043705:Receptor, Adenosine A2A; D051020:bcl-X Protein; D045304:Cytochromes c; D020169:Caspases; D000241:Adenosine