journal contribution
posted on 2023-03-31, 01:47 authored by Sagar Sohoni, Poorva Ghosh, Tianyuan Wang, Sarada Preeta Kalainayakan, Chantal Vidal, Sanchareeka Dey, Purna Chaitanya Konduri, Li Zhang <p>Fig. S3 (A) NSCLC cell lines exhibit a varying degree of migration capabilities. (B) NSCLC cell lines exhibit a varying degree of invasion capabilities. The images shown are cells that had migrated across Transwell inserts (in A) or had crossed invasion chambers coated with Corning Matrigel matrix and also passed Transwell inserts (in B). At least three independent experiments were carried out for every condition. Data are plotted as mean {plus minus} SD. For statistical analysis, the levels in NSCLC cells were compared to the levels in HCC cells with a Welch 2-sample t-test.*, p-value, 0.05, **, p-value < 0.005.</p>
Funding
Cancer Prevention and Research Institute of Texas
History
ARTICLE 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.
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.
