AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C

Ljubica Vucicevic, Maja Misirkic, Kristina Janjetovic, Ljubica Harhaji-Trajkovic, Marko Prica, Darko Stevanovic, Esma Isenovic, Emina Sudar, Mirjana Sumarac-Dumanovic, Dragan Micic, Vladimir Trajkovic
Biochemical Pharmacology 2009 June 1, 77 (11): 1684-93
We investigated the effect of compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), on proliferation and viability of human U251 and rat C6 glioma cell lines. Compound C caused G(2)/M cell cycle block, accompanied by apoptotic glioma cell death characterized by caspase activation, phosphatidylserine exposure and DNA fragmentation. The mechanisms underlying the pro-apoptotic action of compound C involved induction of oxidative stress and downregulation of antiapoptotic molecule Bcl-2, while no alteration of pro-apoptotic Bax was observed. Compound C diminished AMPK phosphorylation and enzymatic activity, resulting in reduced phosphorylation of its target acetyl CoA carboxylase. AMPK activators metformin and AICAR partly prevented the cell cycle block, oxidative stress and apoptosis induced by compound C. The small interfering RNA (siRNA) targeting of human AMPK mimicked compound C-induced G(2)/M cell cycle arrest, but failed to induce oxidative stress and apoptosis in U251 glioma cells. In conclusion, our data indicate that AMPK inhibition is required, but not sufficient for compound C-mediated apoptotic death of glioma cells.

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