AMPK and Akt Determine Apoptotic Cell Death following Perturbations of One-Carbon Metabolism by Regulating ER Stress in Acute Lymphoblastic Leukemia

Abstract

AICAr is a cell-permeable nucleotide that has been used in vivo and in vitro to activate AMPK. Our previous findings have shown that AICAr as a single agent induces dose-and time-dependent growth inhibition in acute lymphoblastic leukemia (ALL) cell lines. In addition, the combination of AICAr with antifolates [methotrexate (MTX) or pemetrexed] has been shown to further potentiate AMPK activation and to lead to greater cytotoxicity and growth inhibition in leukemia and other malignant cell types. Our data presented herein show that sustained endoplasmic reticulum (ER) stress is the predominant mechanism behind the synergistic induction of cell death by the combination of AICAr plus the inhibitor of one-carbon metabolism, MTX, in Bp-and T-ALL, as evidenced by induction of several unfolded protein response markers leading to apoptosis. We also show for the first time that AICAr in combination with MTX significantly induces Akt phosphorylation in ALL. Under these conditions, the concomitant inhibition of Akt, a cellular antagonist of AMPK, leads to further upregulation of AMPK activity and alleviates AICAr plus MTX-induced ER stress and apoptosis. Therefore, we also show that the concomitant activation of AMPK actually rescues the cells from AICAr plus MTX-induced ER stress and apoptosis. Our data suggest that the effects of AMPK activation on cell death or survival differ contextually depending on its signaling alterations with related oncogenic pathways and provide insight into the reported paradoxical proapoptotic versus prosurvival effects of AMPK activation. Mol Cancer Ther; 10(3); 437-47. Ó2011 AACR.

Targeting Energy Metabolic and Oncogenic Signaling Pathways in Triple-negative Breast Cancer by a Novel Adenosine Monophosphate-activated Protein Kinase (AMPK) Activator

“…1C) of LKB1-deficient MDA-MB-231 and LKB1-functional MDA-MB-468 cells with nearly equal potency (IC 50 , 5 and 2 M for MTT and clonogenic assays, respectively). This antiproliferative potency is 3-4 orders-of magnitude higher than that reported for metformin (15) and AICAR (25) in breast cancer cells. Moreover, this LKB1-independent activity of OSU-53 contrasts with the reported insensitivity of MDA-MB-231 cells to metformin because of the lack of LKB1 expression in this cell line (26).…”

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

“…51 Previous investigations have highlighted the cytotoxic potential of the AMPK activator, AICAR in T-ALL and B-ALL cell lines. [52][53][54] However, as far as we know, this is the first report that documents the cytotoxicity of metformin against both T-ALL cell lines and patients lymphoblasts, including cell subsets that could be enriched in LIC. Nevertheless, a word of caution is necessary.…”

Regulation of Death Induction and Chemosensitizing Action of 3-Bromopyruvate in Myeloid Leukemia Cells: Energy Depletion, Oxidative Stress, and Protein Kinase Activity Modulation

“…Because AMPK inactivation by a metabolic inhibitor may be contemplated as an unusual response, and also because Akt and AMPK are thought to be antagonistic kinases (Jin et al, 2007;Lee and Park, 2010;Kuznetsov et al, 2011), we investigated the possible Akt-AMPK interaction in our model system. Hence, HL60 cells were subjected to short treatments (from 15 minutes to 2 hours) with 30 mM 3-BrP, or they were treated for 4 hours with 3-BrP in combination with the PI3K/ Akt inhibitor LY294002.…”