title: AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation.
abstract: The AMP-activated protein kinase agonist AICAR mimics a low intracellular energy state and inhibits the proliferation of cancer cells by different mechanisms, which may depend on the bioenergetic signature of these cells. AICAR can also stimulate mitochondrial biogenesis in myoblasts, neurons and HeLa cells. Yet, whether the reactivation of oxidative phosphorylation biogenesis by AICAR contributes to the growth arrest of cancer cells remains undetermined. To investigate this possibility, we looked at the impact of 24- and 48-hour treatments with 750 μM AICAR on human cancer cell lines (HeLa, DU145, and HEPG2), non-cancer cells (EM64, FM14, and HLF), embryonic cells (MRC5) and Rho(0) cells. We determined the bioenergetic profile of these cells and assessed the effect of AICAR on oxidative phosphorylation biogeneis, cell viability and cell proliferation, ROS generation, mitochondrial membrane potential and apoptosis induction. We also followed possible changes in metabolic regulators such as Akt and Hif1-α stabilization which might participate to the anti-proliferative effect of AICAR. Our results demonstrated a strong and cancer-specific anti-growth effect of AICAR that may be explained by three different modes according to cell type: the first mode included stimulation of the mitochondrial apoptotic pathway however with compensatory activation of Akt and upregulation of oxidative phosphorylation. In the second mode of action of AICAR Akt phosphorylation was reduced. In the third mode of action, apoptosis was activated by different pathways. The sensitivity to AICAR was higher in cells with a low steady-state ATP content and a high proliferation rate.
authors.affiliation: (MRGM) Maladies Rares: Génétique et Métabolisme, Université Victor Segalen, F-33076 Bordeaux, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jose
authors.forename: Etienne
authors.initials: E
authors.lastname: Hébert-Chatelain
authors.forename: Nadège
authors.initials: N
authors.lastname: Bellance
authors.forename: Anaïs
authors.initials: A
authors.lastname: Larendra
authors.forename: Melser
authors.initials: M
authors.lastname: Su
authors.forename: Karine
authors.initials: K
authors.lastname: Nouette-Gaulain
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D009369:Neoplasms / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D012265:Ribonucleotides / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D051058:Oncogene Protein v-akt; C031143:AICA ribonucleotide