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 eIF2α 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.
Highlights
Breast cancer is the most diagnosed malignancy among women worldwide
Our previous study had shown that Betulinic acid (BA) suppressed glycolysis metabolism of breast cancer cells [34]
We found that the extent of wound healing was impaired (Figure 1(e)) and the number of invading cells passing through the membrane was significantly reduced following BA treatment (Figure 1(f))
Summary
Breast cancer is the most diagnosed malignancy among women worldwide. In 2018, it is estimated that 2.1 million new cases will be diagnosed. Breast cancer accounts for cancer occurrences in almost 1 in 4 females and for 11.6% of all sites of malignancies in both men and women [1]. Breast cancer is the leading cause of cancer deaths among women in over 100 countries. There will be 62679 breast cancer deaths globally in 2018, which accounts for 6.6% of all site cancer deaths in both sexes [2, 3]. According to cancer death cause analysis, metastasis is always the leading reason and tremendous endeavor has been dedicated to its underlying mechanisms, such as cancer stem cells, immune depression, and metabolic alteration. Candidate drugs approved for the inhibition of Oxidative Medicine and Cellular Longevity metastasis are very limited, and natural phytochemicals have become an important resource to discover precursors of metastasis inhibitors
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