Negative Regulation of AMP-activated Protein Kinase (AMPK) Activity by Macrophage Migration Inhibitory Factor (MIF) Family Members in Non-small Cell Lung Carcinomas

Stephanie E Brock,Robert A Mitchell,Kavitha Yaddanapudi,Beatriz E Rendon

doi:10.1074/jbc.m112.378299

Stephanie E Brock, Robert A Mitchell + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m112.378299

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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 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.

Highlights

Macrophage migration inhibitory factor (MIF) family members promote AMP-activated protein kinase (AMPK) activation in nontransformed cells
CD74 silencing phenocopies MIF/D-dopachrome tautomerase (D-DT) silencing in inducing AMPK phosphorylation in A549 lung adenocarcinoma cells. These findings suggest that MIF and D-DT, through CD74, cooperate to inhibit AMPK phosphorylation and activity in human non-small cell lung carcinomas (NSCLCs) cell lines
We investigated whether endogenous MIF and/or D-DT is necessary for maximal, steady-state S6 kinase (S6K) activation in lung adenocarcinoma cell lines

Summary

Background

Macrophage migration inhibitory factor (MIF) family members promote AMP-activated protein kinase (AMPK) activation in nontransformed cells. Our data 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 ␤-dependent AMPK activation. Combined, these studies indicate that MIF and D-DT cooperate to inhibit AMPK activation in an LKB1-independent manner. Because the two most commonly used AMPK activators, metformin and 5-amino-1-␤-D-ribofuranosyl-imidazole-4-carboxamide (AICAR), have anti-cancer activities [19, 20] but are ineffective at inducing AMPK activation and subsequent tumor suppression in LKB1 mutant cells [21, 22], the discovery of unique LKB1-independent AMPK activators would be expected to have a significant impact on NSCLC disease management for clinicians

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION