Background/Aims: Accumulating evidence has pointed to AMP-activated protein kinase (AMPK) as an inducer of apoptosis in a variety of cancer cells. The present study aimed at understanding AMPK signals for adenosine-induced HuH-7 cell apoptosis. Methods: Cell viability, AMPK activity, mitochondrial membrane potentials, phosphorylation of Bcl-XL, in situ DIABLO mobilizations, and caspase-3 activity were monitored in HuH-7 cells. Plasmid DNAs for DIABLO-GFP, mutant Bcl-XL, dominant negative mutant AMPKα2 and the siRNAs to silence the AMPKα1 or AMPKα2 targeted gene were constructed and transfected. Results: Adenosine or the AMPK activator AICAR induced apoptosis in HuH-7 cells, and no synergistic effect was obtained with co-treatment. Adenosine activated AMPK, to phosphorylate Bcl-XL. Adenosine or AICAR disrupted mitochondrial membrane potentials, and the effect was inhibited by knocking-down AMPKα1 and/or AMPKα2, expressing dominant negative mutant AMPKα2 or mutant Bcl-XL lacking Ser/Thr phosphorylation sites. AICAR stimulated DIABLO release from the mitochondria, and the release was suppressed by expressing the mutant Bcl-XL. AICAR activated caspase-3, which was also inhibited by expressing the mutant Bcl-XL. Conclusion: Adenosine activates AMPK, to disrupt mitochondrial membrane potentials through Bcl-XL phosphorylation, allowing DIABLO release from the mitochondria, as a factor for caspase-3 activation to induce HuH-7 cell apoptosis.

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