Abstract 2111: Increased heme influx dictates tumorigenic functions of non-small cell lung cancer cells

Abstract

Abstract Heme, iron protoporphyrin IX, is a central metabolic and signaling molecule that regulates diverse molecular and cellular processes relating to oxygen utilization and metabolism. Heme serves as a cofactor or a prosthetic group for complexes II, III, and IV in electron transport chain. Hence, it has a direct role in oxidative phosphorylation and energy generation in cells. Most human cells can synthesize and uptake heme from circulation. A number of epidemiological studies have shown that high heme intake is associated with an increased risk of cancer, including lung cancer. Our lab has previously shown that an array of non-small cell lung cancer cells (NSCLCs) exhibit high heme synthesis and uptake. This increased heme flux correlates with an enhanced oxygen consumption and ATP production. NSCLCs also exhibited significantly elevated levels of hemoproteins and mitochondrial biogenesis proteins compared to normal lung cell lines. Expression levels of these proteins correlate with increased oxygen consumption and the total heme content of NSCLCs suggesting a possible role of heme in energy metabolism and mitochondrial biogenesis. In order to assess the involvement of heme in tumorigenicity of the NSCLC cell lines, we overexpressed heme synthesis enzyme, ALAS1 or heme transporters, HCP1 or HRG1 using lentivirus system. NSCLC cell lines A549 and H1299 were infected with a lentivirus carrying ALAS1 or HCP1 or HRG1 plasmid. Stable clones were obtained with antibiotic selection and checked for overexpression with western-blots. Cells overexpressing ALAS1, HCP1 and HRG1 showed significantly higher rates of heme influx as well as intensified oxygen consumption and ATP formation compared to eGFP controls. Tumorigenic properties such as invasion, migration and colony formation were also found to be significantly increased in these cell lines compared to their eGFP counterparts. Subcutaneous xenografts generated with overexpression cell lines also showed significantly high tumor growth rates and mass compared to eGFP controls. Our data from both in vitro and in vivo experiments show that heme directly improves the tumorigenic properties of NSCLC cells by substantially improving the respiration rates and energy metabolism. Citation Format: Sagar Shashikant Sohoni, Poorva Ghosh, Li Zhang. Increased heme influx dictates tumorigenic functions of non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2111.