Abstract
Tumors of human non-small cell lung cancer (NSCLC) are heterogeneous but exhibit elevated glycolysis and glucose oxidation relative to benign lung tissues. Heme is a central molecule for oxidative metabolism and ATP generation via mitochondrial oxidative phosphorylation (OXPHOS). Here, we showed that levels of heme synthesis and uptake, mitochondrial heme, oxygen-utilizing hemoproteins, oxygen consumption, ATP generation, and key mitochondrial biogenesis regulators were enhanced in NSCLC cells relative to nontumorigenic cells. Likewise, proteins and enzymes relating to heme and mitochondrial functions were upregulated in human NSCLC tissues relative to normal tissues. Engineered heme-sequestering peptides (HSP) reduced heme uptake, intracellular heme levels, and tumorigenic functions of NSCLC cells. Addition of heme largely reversed the effect of HSPs on tumorigenic functions. Furthermore, HSP2 significantly suppressed the growth of human NSCLC xenograft tumors in mice. HSP2-treated tumors exhibited reduced oxygen consumption rates (OCR) and ATP levels. To further verify the importance of heme in promoting tumorigenicity, we generated NSCLC cell lines with increased heme synthesis or uptake by overexpressing either 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 displayed elevated OCRs and ATP levels. These data show that elevated heme flux and function underlie enhanced OXPHOS and tumorigenicity of NSCLC cells. Targeting heme flux and function offers a potential strategy for developing therapies for lung cancer. SIGNIFICANCE: These findings show that elevated heme availability due to increased heme synthesis and uptake causes intensified oxygen consumption and ATP generation, promoting tumorigenic functions and tumor growth in NSCLC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/10/2511/F1.large.jpg.
Highlights
IntroductionAbout 85% of cases are non–small cell lung cancer (NSCLC)
Lung cancer is the leading cause of cancer-related deaths in the United States [1]
Heme biosynthesis (Fig. 1A) and uptake (Fig. 1B) were both increased in non–small cell lung cancer (NSCLC) cell lines and NL20-TA, the increases varied considerably among different cell lines
Summary
About 85% of cases are non–small cell lung cancer (NSCLC). Several chemotherapeutic and targeted therapeutic agents are approved for treating lung cancer, the 5-year survival rate remains 18%. The effectiveness of targeted therapies for lung cancer is lowered by the presence of multiple driver genes and intratumoral genetic heterogeneity [2]. Three PD-1/PD-L1 checkpoint inhibitors, nivolumab, pembrolizumab, and atezolizumab, generally extend median overall survival by about 3 months for second-line treatment of advanced NSCLC, compared with docetaxel alone [3,4,5]. In the front-line setting, the median progression-free survival extends from 6.0 months with platinum-doublet chemotherapy to 10.3 months with pembrolizumab in patients with untreated NSCLC characterized by a high level of PD-L1 expression [6]. Alternative therapeutic strategies are still needed for lung cancer treatment
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