Abstract 5264: Negative regulation of AMPK-dependent metabolic-stress pathways by MIF and D-DT in non-small cell lung carcinoma.

Abstract

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 pro-tumorigenic functions in non-small cell lung carcinoma (NSCLC) 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-DT's AMPK activating properties in non-transformed cells, MIF and D-DT cooperatively act to inhibit steady state phosphorylation and activation of AMPK in LKB1 wildtype 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 [[Unsupported Character - Symbol Font β]] (CaMKK[[Unsupported Character - Symbol Font β]])-dependent AMPK activation. Combined, these studies indicate that MIF and D-DT cooperate to inhibit AMPK activation in an LKB1-independent manner. This suggests that MIF and D-DT promote a unique and well conserved adaptation pathway that is usurped by the malignant cells in order to counter metabolic stress-induced, AMPK-dependent, tumor suppression. Importantly, because the LKB1 tumor suppressor locus is mutated in over 30% of NSCLC lesions rendering these tumors insensitive to AMPK-dependent growth suppression, the identification of unique AMPK agonists would be expected to have a tremendous impact on NSCLC disease management for clinicians. Taken together, simultaneous therapeutic targeting of both MIF and D-DT represents an innovative and clinically efficacious approach to re-activating metabolic stress-induced tumor suppression in NSCLC malignant lesions. Citation Format: Stephanie Brock, Beatriz Rendon, Kavitha Yaddanapudi, Robert Mitchell. Negative regulation of AMPK-dependent metabolic-stress pathways by MIF and D-DT in non-small cell lung carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5264. doi:10.1158/1538-7445.AM2013-5264