Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway. (19th August 2019)

• Record Type: Journal Article
• Authors: Zheng, Yifeng; Liu, Pengxi; Wang, Neng; Wang, Shengqi; Yang, Bowen; Li, Min; Chen, Jianping; Situ, Honglin; Xie, Meiqi; Lin, Yi; Wang, Zhiyu
• Other Names: Lisanti Michael P. Guest Editor.
• Is Part Of: Oxidative medicine and cellular longevity. Volume 2019(2019)
• Publication Date: 2019-08-19
• Subjects: Oxidative stress -- Periodicals; Cells -- Aging -- Periodicals; Cells -- Aging; Oxidative stress; Oxidative Stress -- Periodicals; Cell Aging -- Periodicals; Periodicals; 611.0181
• DOI: 10.1155/2019/8781690
• Languages: English
• ISSNs: 1942-0900

Abstract

Abstract : Targeting aberrant metabolism is a promising strategy for inhibiting cancer growth and metastasis. Research is now geared towards investigating the inhibition of glycolysis for anticancer drug development. Betulinic acid (BA) has demonstrated potent anticancer activities in multiple malignancies. However, its regulatory effects on glycolysis and the underlying molecular mechanisms are still unclear. BA inhibited invasion and migration of highly aggressive breast cancer cells. Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins. In this study, glucose-regulated protein 78 (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis. Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK. Subsequent phosphorylation of eIF2 α led to the inhibition of β -catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis. Coimmunoprecipitation assay revealed that BA interrupted the binding between GRP78 and PERK, thereby initiating the glycolysis inhibition cascade. Finally, the lung colonization model validated that BA inhibited breast cancer metastasis in vivo, as well as suppressed the expression of aerobic glycolysis-related proteins. In conclusion, our study not only provided a promising drug for aerobic glycolysis inhibition but also revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during tumor metastasis.