Increased Heme Flux and Mitochondrial Resporation Enhance Tumorigenic Functions in Non-Small Cell Lung Cancer Cells
Lung cancer is the leading cause of cancer related deaths in United States, and about 85% of the cases are Non-small cell lung cancer (NSCLC). Many targeted therapies have been developed to treat lung cancer. Unfortunately, however statistical data over the past two decades suggest only a slight improvement in a patient’s survival rate after diagnosis. Clonal evolution and tumor heterogeneity are the major obstacles in designing effective targeted treatments against cancer. To create more comprehensive treatments, emerging therapies target bioenergetic pathways of cancer cells. Like normal cells, cancer cells can generate energy only through glycolysis and oxidative phosphorylation. Notably, a number of studies have shown that many types of cancer cells rely heavily on mitochondrial respiration. Tumors of human non-small cell lung cancer (NSCLC) are heterogeneous but exhibit elevated glycolysis and glucose oxidation relative to benign lung. Heme is a central molecule for oxidative metabolism and ATP generation via mitochondrial oxidative phosphorylation (OXPHOS). Here, we have found that non-small cell lung cancer cells show elevated levels of heme synthesis and uptake, mitochondrial heme, oxygen-utilizing hemoproteins, oxygen consumption, ATP generation, and key mitochondrial biogenesis regulators relative to non-tumorigenic cells. Likewise, proteins and enzymes relating to heme and mitochondrial functions are found to be upregulated in human NSCLC tissues relative to normal tissues. Hence, we believe altering heme availability can be a useful strategy in treatment of highly heterogenous cancers. In order to seqester extra-cellular heme we engineered heme-sequestering peptides (HSPs). We observed that treatment with HSPs significantly reduce heme uptake, intracellular heme levels, and tumorigenic functions of NSCLC cells. This effect of HSPs is specific to heme as addition of heme largely reversed the effect of HSPs on tumorigenic functions. Furthermore, we also observed that HSP2 significantly suppresses the growth of human NSCLC xenograft tumors in mice. HSP2-treated tumors showed lowered oxygen consumption rates and ATP levels. To further verify the importance of heme in promoting tumorigenicity, we generated NSCLC cell lines with increased heme synthesis or uptake, which result from overexpression of the rate-limiting heme synthesis enzyme ALAS1 or uptake protein SLC48A1, respectively. These cells exhibited enhanced migration and invasion and accelerated tumor growth in mice. Notably, tumors formed by cells with increased heme synthesis or uptake also have elevated oxygen consumption rates and ATP levels. Our data show that elevated heme flux and function underlie enhanced OXPHOS and tumorigenicity of NSCLC cells. Therefore, targeting heme flux and function offers a novel strategy for developing lung cancer therapy.