Negative Regulation of AMP-activated Protein Kinase (AMPK) Activity by Macrophage Migration Inhibitory Factor (MIF) Family Members in Non-small Cell Lung Carcinomas |
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Authors: | Stephanie E. Brock Beatriz E. Rendon Kavitha Yaddanapudi Robert A. Mitchell |
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Affiliation: | From the ‡Molecular Targets Program, J. G. Brown Cancer Center, and ;the §Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky 40202 |
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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 Ca2+/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. |
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Keywords: | AMP-activated Kinase (AMPK) Cancer Biology Cytokine Action LKB Lung Cancer GLUT4 Glucose Glutathione Reactive Oxygen Species |
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