Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics
Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrate...
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doaj-af1647ebe33643389d5851067a3473f72020-11-25T02:23:40ZengMDPI AGCancers2072-66942020-04-011291391310.3390/cancers12040913Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated BioenergeticsHye-Young Min0Honglan Pei1Seung Yeob Hyun2Hye-Jin Boo3Hyun-Ji Jang4Jaebeom Cho5Ji Hye Kim6Jaekyoung Son7Ho-Young Lee8Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, KoreaCreative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, KoreaCreative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, KoreaCreative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, KoreaCreative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, KoreaCreative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, KoreaDepartment of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul 05505, KoreaDepartment of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul 05505, KoreaCreative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, KoreaMetabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.https://www.mdpi.com/2072-6694/12/4/913gracillinbreast cancerlung cancerglycolysisoxidative phosphorylationphosphoglycerate kinase 1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hye-Young Min Honglan Pei Seung Yeob Hyun Hye-Jin Boo Hyun-Ji Jang Jaebeom Cho Ji Hye Kim Jaekyoung Son Ho-Young Lee |
spellingShingle |
Hye-Young Min Honglan Pei Seung Yeob Hyun Hye-Jin Boo Hyun-Ji Jang Jaebeom Cho Ji Hye Kim Jaekyoung Son Ho-Young Lee Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics Cancers gracillin breast cancer lung cancer glycolysis oxidative phosphorylation phosphoglycerate kinase 1 |
author_facet |
Hye-Young Min Honglan Pei Seung Yeob Hyun Hye-Jin Boo Hyun-Ji Jang Jaebeom Cho Ji Hye Kim Jaekyoung Son Ho-Young Lee |
author_sort |
Hye-Young Min |
title |
Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics |
title_short |
Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics |
title_full |
Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics |
title_fullStr |
Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics |
title_full_unstemmed |
Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics |
title_sort |
potent anticancer effect of the natural steroidal saponin gracillin is produced by inhibiting glycolysis and oxidative phosphorylation-mediated bioenergetics |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-04-01 |
description |
Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics. |
topic |
gracillin breast cancer lung cancer glycolysis oxidative phosphorylation phosphoglycerate kinase 1 |
url |
https://www.mdpi.com/2072-6694/12/4/913 |
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