Abstract 3244: Compensatory function of the homologous proteins MIF and D-DT in regulation of AMPK-dependent metabolic-stress pathways in non-small cell lung carcinoma

Abstract

Abstract Macrophage migration inhibitory factor (MIF) is over-expressed in most solid malignancies and is important for many pro-tumorigenic pathways. Several studies reveal that genetic deletion or inhibition of MIF results in anti-cancer phenotypes, but these phenotypes are not nearly as profound as one would anticipate given its reported activities. We recently discovered that MIF's only related family member, D-dopachrome tautomerase (D-DT), functionally compensates for MIF-dependent promotion of angiogenic potential in non-small cell lung carcinoma (NSCLC). This finding not only provides an explanation for why MIF individual targeting has not provided more efficacious anti-cancer activities, but also suggests that therapeutic targeting of MIF and D-DT simultaneously may provide a highly effective and novel new class of anti-lung cancer pharmacologic agents. Here we present further evidence of the important cooperative function of these two homologous proteins in NSCLC cells. We reveal a strong collaborative effect of MIF and D-DT on the negative regulation of AMP-activated protein kinase (AMPK) activation. AMPK is phosphorylated by the tumor suppressor, LKB1, in response to metabolic stress, resulting in AMPK-dependent p53 activation and mTOR inhibition. We show that while siRNA-mediated knockdown of endogenous MIF or D-DT individually has modest effects on AMPK activation in NSCLC cells, combined knockdown of both MIF and D-DT results in a significant activation of AMPK-dependent regulation of p53 and mTOR pathways. Importantly, this re-activation of AMPK by MIF and D-DT occurs in LKB1 mutant NSCLC cell lines. In addition, overexpression of MIF or D-DT alone by adenoviral delivery causes a substantial reduction in p53 expression, with a dramatic increase in mTOR pathway activation. Our findings suggest 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. 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: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3244. doi:1538-7445.AM2012-3244