Abstract
AMP-activated protein kinase (AMPK) is a nutrient- and metabolic stress-sensing enzyme activated by the tumor suppressor kinase, LKB1. Because macrophage migration inhibitory factor (MIF) and its functional homolog, d-dopachrome tautomerase (d-DT), have protumorigenic functions in non-small cell lung carcinomas (NSCLCs) but have AMPK-activating properties in nonmalignant cell types, we set out to investigate this apparent paradox. Our data now suggest that, in contrast to MIF and d-DTs AMPK-activating properties in nontransformed cells, MIF and d-DT act cooperatively to inhibit steady-state phosphorylation and activation of AMPK in LKB1 wild type and LKB1 mutant human NSCLC cell lines. Our data further indicate that MIF and d-DT, acting through their shared cell surface receptor, CD74, antagonize NSCLC AMPK activation by maintaining glucose uptake, ATP production, and redox balance, resulting in reduced Ca(2+)/calmodulin-dependent kinase kinase β-dependent AMPK activation. Combined, these studies indicate that MIF and d-DT cooperate to inhibit AMPK activation in an LKB1-independent manner.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Acetylcysteine / pharmacology
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / metabolism
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Deoxyglucose / pharmacology
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Enzyme Activation / drug effects
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Free Radical Scavengers / pharmacology
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Glucose / pharmacokinetics
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Glucose / pharmacology
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / metabolism
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Humans
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Immunoblotting
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / metabolism*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Macrophage Migration-Inhibitory Factors / genetics
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Macrophage Migration-Inhibitory Factors / metabolism*
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Mutation
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Oxidation-Reduction / drug effects
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism
Substances
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Antigens, Differentiation, B-Lymphocyte
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Free Radical Scavengers
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Histocompatibility Antigens Class II
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Macrophage Migration-Inhibitory Factors
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Reactive Oxygen Species
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invariant chain
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Deoxyglucose
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Protein Serine-Threonine Kinases
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STK11 protein, human
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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Intramolecular Oxidoreductases
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dopachrome isomerase
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Glucose
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Acetylcysteine