Abstract 5490: Targeting mitochondrial function in lung tumor growth and progression

Abstract

Abstract Contrary to Warburg's hypothesis, mitochondrial oxidative phosphorylation contributes significantly to fuel cancer cells. Besides oxidative phosphorylation, mitochondria are also involved in heme synthesis. Heme serves as a prosthetic group for several proteins that constitute the complexes of mitochondrial electron transport chain. Therefore, heme plays a pivotal role in mitochondrial oxidative phosphorylation. Recently, our lab demonstrated that non-small cell lung cancer (NSCLC) cells exhibit intensified mitochondrial respiration. Targeting increased mitochondrial respiration with therapeutic agents effectively hampers proliferation of NSCLC cells in vitro. Previous results from our lab also demonstrated that NSCLC cell lines exhibited elevated heme synthesis, heme uptake, and expression of hemoproteins. These results suggest that increased mitochondrial respiration is facilitated by excess intracellular heme that is incorporated into hemoproteins. Our study aims to assess whether targeting mitochondrial function and heme synthesis affects NSCLC tumor growth and progression in vivo. To this end, luciferase-expressing NSCLC cells were implanted in NOD/SCID mice to generate lung orthotopic xenografts. The mice bearing orthotopically implanted NSCLC tumors were treated with various agents that target mitochondrial function alone (MTA1 or MTA2) and in combination with heme synthesis inhibitor. Tumor growth was monitored by noninvasive bioluminescence imaging (BLI). Our BLI data demonstrated that there was a significant reduction in radiance in mice that received the mitochondria-targeting agent alone (MTA1) and a combination of mitochondrial-targeting agents (MTA1 and MTA2). BLI data also demonstrated that there was a considerable reduction in radiance in mice that received combination of MTA and heme synthesis inhibitor. Treatments with combination of MTAs and heme inhibitor are under way. Our Immunohistochemistry data indicate that there was a reduction in expression of proteins involved in heme transport as well as hemoproteins involved in mitochondrial respiration in mice treated with the mitochondria-targeting agent. Our results suggest that targeting mitochondria significantly inhibits lung tumor growth by affecting proteins involved in heme synthesis and degradation, and consequently decreasing mitochondrial respiration. Citation Format: Sarada Preeta Kalainayakan, Poorva Ghosh, Sancharika Dey, Li Liu, Li Zhang. Targeting mitochondrial function in lung tumor growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5490.