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Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis

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 repro...

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Autores principales: Yang, Yuping, Liu, Lingling, Sun, Jinghui, Wang, Shu, Yang, Zhongyuan, Li, Honghui, Huang, Na, Zhao, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959795/
https://www.ncbi.nlm.nih.gov/pubmed/33732648
http://dx.doi.org/10.3389/fonc.2021.629543
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author Yang, Yuping
Liu, Lingling
Sun, Jinghui
Wang, Shu
Yang, Zhongyuan
Li, Honghui
Huang, Na
Zhao, Wei
author_facet Yang, Yuping
Liu, Lingling
Sun, Jinghui
Wang, Shu
Yang, Zhongyuan
Li, Honghui
Huang, Na
Zhao, Wei
author_sort Yang, Yuping
collection PubMed
description 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.
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spelling pubmed-79597952021-03-16 Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis Yang, Yuping Liu, Lingling Sun, Jinghui Wang, Shu Yang, Zhongyuan Li, Honghui Huang, Na Zhao, Wei Front Oncol Oncology 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. Frontiers Media S.A. 2021-02-24 /pmc/articles/PMC7959795/ /pubmed/33732648 http://dx.doi.org/10.3389/fonc.2021.629543 Text en Copyright © 2021 Yang, Liu, Sun, Wang, Yang, Li, Huang and Zhao http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Yang, Yuping
Liu, Lingling
Sun, Jinghui
Wang, Shu
Yang, Zhongyuan
Li, Honghui
Huang, Na
Zhao, Wei
Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis
title Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis
title_full Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis
title_fullStr Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis
title_full_unstemmed Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis
title_short Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis
title_sort deoxypodophyllotoxin inhibits non-small cell lung cancer cell growth by reducing hif-1α-mediated glycolysis
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959795/
https://www.ncbi.nlm.nih.gov/pubmed/33732648
http://dx.doi.org/10.3389/fonc.2021.629543
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