%0 Journal Article
%T Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain
%A Purna Mukherjee
%A Tiernan J Mulrooney
%A Jeremy Marsh
%A Derek Blair
%A Thomas C Chiles
%A Thomas N Seyfried
%J Molecular Cancer
%D 2008
%I BioMed Central
%R 10.1186/1476-4598-7-37
%X Here we show that energy stress differentially affects AMPK phosphorylation and cell-death in brain tumor tissue and in tissue from contra-lateral normal brain. We compared TSC2 deficient CT-2A mouse astrocytoma cells with syngeneic normal astrocytes that were grown under identical condition in vitro. Energy stress induced by glucose withdrawal or addition of 2-deoxyglucose caused more ATP depletion, AMPK phosphorylation and apoptosis in CT-2A cells than in the normal astrocytes. Under normal energy conditions pharmacological stimulation of AMPK caused apoptosis in CT-2A cells but not in astrocytes. TSC2 siRNA treated astrocytes are hypersensitive to apoptosis induced by energy stress compared to control cells. AMPK phosphorylation and apoptosis were also greater in the CT-2A tumor tissue than in the normal brain tissue following implementation of dietary energy restriction. Inefficient mTOR and TSC2 signaling, downstream of AMPK, is responsible for CT-2A cell-death, while functional LKB1 may protect normal brain cells under energy stress.Together these data demonstrates that AMPK phosphorylation induces apoptosis in mouse astrocytoma but may protect normal brain cells from apoptosis under similar energy stress condition. Therefore, using activator of AMPK along with glycolysis inhibitor could be a potential therapeutic approach for TSC2 deficient human malignant astrocytoma.AMP-activated protein kinase (AMPK) is a primary regulator of the cellular response to lowered ATP levels in eukaryotic cells [1,2]. AMPK is a serine/threonine protein kinase and a member of the Snf1/AMPK protein kinase family [1]. The activity of AMPK requires phosphorylation of the alpha subunit on Thr-172 in its activation loop by one or more upstream kinases (AMPKK) [3-5]. AMPK phosphorylation down regulates ATP consuming processes like the synthesis of fatty acids, cholesterol, and proteins, while up-regulating ATP producing catabolic pathways like fatty acid oxidation and glucose uptake. P
%U http://www.molecular-cancer.com/content/7/1/37