Abstract
Recently, targeting cancer stem cells (CSCs) metabolism is becoming a promising therapeutic approach to improve cancer treatment outcomes. However, knowledge of the metabolic state of CSCs in small cell lung cancer is still lacking. In this study, we found that CSCs had significantly lower oxygen consumption rate and extracellular acidification rate than non-stem cancer cells. Meanwhile, this subpopulation of cells consumed less glucose, produced less lactate and maintained lower ATP levels. We also revealed that CSCs could produce more ATP through mitochondrial substrate-level phosphorylation during respiratory inhibition compared with non-stem cancer cells. Furthermore, they were more sensitive to suppression of oxidative phosphorylation. Therefore, oligomycin (inhibitor of oxidative phosphorylation) could severely impair sphere-forming and tumor-initiating abilities of CSCs. Our work suggests that CSCs represent metabolically inactive tumor subpopulations which sustain in a state showing low metabolic activity. However, mitochondrial substrate-level phosphorylation of CSCs may be more active than that of non-stem cancer cells. Moreover, CSCs showed preferential use of oxidative phosphorylation over glycolysis to meet their energy demand. These results extend our understanding of CSCs metabolism, potentially providing novel treatment strategies targeting metabolic pathways in small cell lung cancer.
Highlights
Small cell lung cancer (SCLC) is a type of highly aggressive tumor which represents about 15% of all lung cancer cases [1,2]
Uncoupling of oxidative phosphorylation (OXPHOS) using FCCP increased oxygen consumption rate (OCR) to maximum in both cell subpopulations, with a less pronounced response being observed in Urokinase-type plasminogen activator receptor (uPAR)+ cells (Fig 1B and 1C)
Even if the basal extracellular acidification rate (ECAR) is low in uPAR+ cells, it is possible that uPAR+ cells might upregulate glycolysis when mitochondrial OXPHOS is blocked [16]
Summary
Small cell lung cancer (SCLC) is a type of highly aggressive tumor which represents about 15% of all lung cancer cases [1,2]. Patients with SCLC have an initial good clinical response to chemo- radiation therapy, most patients treated with these approaches will relapse. Metabolism of CSCs in SCLC Cell Line H446 after a short period[3]. This can in part be attributed to failure to eradicate cancer stem cells (CSCs), which have the ability to self-renew, to differentiate into multiple lineages and to initiate tumors in immunocompromised mice[4,5]. CSCs are believed to be more resistant to radio- and chemo-therapy than the non-stem cancer cells[5]. It is crucial to develop promising therapeutic strategies targeting CSCs by overcoming their drug resistance
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