IA10 Novel Metabolic Functions for Redox Regulators in Non-Small Cell Lung Cancer

Abstract

Redox regulators are emerging as critical mediators of lung tumorigenesis. Notably, NRF2 and its negative regulator KEAP1 are commonly mutated in human lung cancers. These mutations lead to NRF2 accumulation and constitutive expression of NRF2 target genes, many of which are at the interface of antioxidant function and anabolic processes that support cellular proliferation. However, much of our understanding about the regulation of, and requirement for, these metabolic alterations comes from studies in cell culture. To understand the deregulation of cellular metabolism by NRF2 in vivo, we generated genetically engineered, conditional murine alleles of the NRF2D29H and KEAP1R554Q mutations found in human NSCLC, and generated lung tumor models harboring these mutations. Our data from these models suggest that not all NRF2-regulated metabolic alterations are favorable and that NRF2 activation results in metabolic liabilities that must be overcome during tumorigenesis. While NRF2 primarily supports the cytoplasmic antioxidant system, the mitochondrial antioxidant system is also critical to mitigate the reactive oxygen species (ROS) generated as a byproduct of the robust and complex mitochondrial metabolism characteristic of lung tumors. Nicotinamide nucleotide transhydrogenase (NNT) is known to sustain mitochondrial antioxidant capacity through the generation of NADPH; however, its function in non-small cell lung cancer (NSCLC) has not been established. To determine the importance of NNT activity to lung tumorigenesis, we studied lung tumor mice lacking NNT. We found that NNT expression significantly enhanced tumor formation as well as tumor aggressiveness in mouse models of lung tumor initiation and progression. Interestingly, while NNT significantly contributed to the NADPH:NADP+ ratio in lung cancer cell lines, NNT loss did not lead to global oxidative stress. Rather, NNT supported the activities of enzymes containing iron-sulfur (Fe-S) clusters, including aconitase and the electron transport chain subunits. Collectively, our work demonstrates the importance of redox regulators to lung tumor biology and uncovers distinct metabolic states arising from their perturbation.