Abstract
Cancer cell proliferation is a metabolically demanding process that requires high rate of glycolysis to support anabolic growth. Deoxypodophyllotoxin (DPT) is a natural flavonolignan with various pharmacological activities, including antitumor effect. However, whether DPT affects the metabolic reprogramming of cancer cells is unknown. The purpose of this study is to investigate the role of DPT on non-small cell lung cancer (NSCLC) and to explore whether HIF-1α-mediated glycolysis is involved in its mechanism of action.The level of HIF-1α mRNA and protein in NSCLC cells following DPT treatment was detected using qRT-PCR and western blotting, respectively. Cell Counting Kit-8 (CCK-8) and caspase-3 activity assays were performed to analyze cell proliferation and apoptosis. The underlying molecular mechanism was identified by dual luciferase assay, Western blotting, qRT-PCR, glucose consumption, lactate production, and immunoprecipitation. A murine NSCLC model was used to clarify the effect of DPT treatment on tumor cell proliferation. Our findings showed that DPT treatment inhibited NSCLC cell growth in a dose- and time-dependent manner. Further analysis suggested that DPT treatment inhibited HIF-1α signaling pathway by Parkin-mediated protein degradation in NSCLC cells. DPT treatment significantly decreased glucose consumption and lactate production. In addition, DPT treatment reduced the expression of HIF-1α target genes, including GLUT1, HK2 and LDHA, resulting in reduction in glycolysis. We further revealed that DPT-induced cell growth inhibition and increased glucose and lactate levels could be reversed by overexpressing HIF-1α. Additionally, we found that DPT repressed NSCLC growth and GLUT1, HK2 and LDHA expression in vivo. Overall, this study suggested that DPT inhibited NSCLC growth by preventing HIF-1α-mediated glycolysis.
Highlights
Lung cancer is the most frequently diagnosed cancer and its incidence has been increasing in recent years [1, 2]
To assess the effect of DPT on lung cancer cells, A549, SKMES-1, H460 and SPC-A1 cellswere treated with various concentrations of DPT for the indicated time periods, and Cell Counting Kit-8 (CCK-8) assays were performed to measure cell viability
These findings indicated that DPT may be a potential drug for non-small cell lung cancer (NSCLC) treatment
Summary
Lung cancer is the most frequently diagnosed cancer and its incidence has been increasing in recent years [1, 2]. Lung cancer remains a leading cause of cancer-associated mortality for men and women worldwide [1]. The development of lung cancer is a multistep process involving alterations in oncogenes and tumor suppressor genes, and alsoother factors such as alcohol consumption, smoking, pathogenic infections and genetic factors [3,4,5]. NSCLC accounts for over 80% of all lung cancer cases.Because the onset of NSCLC is asymptomatic,NSCLC is usually diagnosed in late clinical stages when surgical resection is not possible. The current prognosis of patients with NSCLC is very poor with a 5-year overall survival (OS) rate of only 10% [6, 7]. There is an urgent need to find novel and effective means for the treatment of NSCLC
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