Abstract B31: Disruption of Folliculin interacting protein-1 modulates Myc-driven metabolism, increasing cell death following metabolic stress

Folliculin interacting protein-1 (Fnip1) is a cytoplasmic protein originally discovered through its interaction with Folliculin (Flcn), a tumor suppressor mutated in the rare fibrofolliculoma disorder Birt-Hogg Dubé syndrome. Fnip1 and Flcn both interact with the master metabolic regulator AMP kinase (AMPK). Our previous studies have shown that Fnip1 is required for the development of B-cells past the late pre-B stage (Park et al Immunity 2012) and for the development invariant natural killer T (iNKT) cells in the thymus (Park et al PNAS 2014). Fnip1 deficiency also prevented the development of B cell lymphoma in Eµ-Myc transgenic mice. Fnip1 deficient immune cells exhibited hyperactivation of mTORC1 concurrent with increased activation of AMPK. In this study, we examined the potential efficacy of Fnip1 disruption in cancer by disrupting Fnip1 in primary mouse and human B cell lines overexpressing the Myc oncogene. We show that constitutive depletion of Fnip1 in primary pre-B cells, conditional knockdown of Fnip1 in primary mouse mature B cells using the Cre-loxP system, or siRNA-mediated depletion of endogenous FNIP1 from a human B cell line expressing a conditional Myc allele, increase oxidative phosphorylation and Myc-induced glycolysis, which support cell division. Disruption of Fnip1 increases death of primary murine pre-B Eµ-Myc cells and human B cell lines in response to nutrient deprivation and chemotherapeutic drugs in vitro. Mass spectrometric analysis of a human B cell line depleted of Fnip1 reveals significant alterations in metabolites involved in glutaminolysis, glycolysis, antioxidant and serine biosynthesis pathways. These results suggest that inhibition of Fnip1 may provide a novel strategy to increase death of lymphoma cells in response to cytotoxic and metabolic stress. Citation Format: Julita A. Ramirez, Mark Tsang, Heon Park, Daciana Margineantu, Haiwei Gu, Daniel Raftery, David M. Hockenbery, Brian M. Iritani. Disruption of Folliculin interacting protein-1 modulates Myc-driven metabolism, increasing cell death following metabolic stress. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B31.