Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics

Cancers

Hyun-Ji Jang¹  Hye-Jin Boo¹  Ho-Young Lee¹  SeungYeob Hyun¹  Jaebeom Cho¹  Hye-Young Min¹  Honglan Pei¹  JiHye Kim²  Jaekyoung Son² 

[1] Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Korea;Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul 05505, Korea;

关键词: gracillin;    breast cancer;    lung cancer;    glycolysis;    oxidative phosphorylation;    phosphoglycerate kinase 1;   

DOI  :  10.3390/cancers12040913

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown