Abstract
The aberrant energy homeostasis that characterized by high rate of energy production (glycolysis) and energy consumption (mRNA translation) is associated with the development of cancer. As mammalian target of rapamycin (mTOR) is a critical regulator of aberrant energy homeostasis, it is an attractive target for anti-tumor intervention. The flavonoid compound Icariside II (IS) is a natural mTOR inhibitor derived from Epimedium. Koreanum. Herein, we evaluate the effect of IS on aberrant energy homeostasis. The reduction of glycolysis and mRNA translation in U2OS (osteosarcoma), S180 (fibrosarcoma) and SW1535 (chondrosarcoma) cells observed in our study, indicate that, IS inhibits aberrant energy homeostasis. This inhibition is found to be due to suppression of mammalian target of rapamycin complex 1 (mTORC1)-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) axis through blocking the assembly of mTORC1. Furthermore, IS inhibits the cap-dependent translation of c-myc through mTORC1-4E-BP1 axis which links the relationship between mRNA translation and glycolysis. Inhibition of aberrant energy homeostasis by IS, contributes to its in vitro and in vivo anti-proliferation activity. These data indicate that IS disrupts aberrant energy homeostasis of sarcoma cells through suppression of mTORC1-4E-BP1 axis, providing a novel mechanism of IS to inhibit cell proliferation in sarcoma cells.
Highlights
Sarcomas are mesenchymal malignancies that exhibit a higher percentage of overall cancer morbidity and mortality in children and adolescents than in adults [1]
Www.impactjournals.com/oncotarget mammalian target of rapamycin complex 1 (mTORC1) is recognized as a key metabolic sensor that integrates nutrient, the cellular energy status and growth factor levels, by promoting protein synthesis and activating bioenergetic processes [54]
We reported that, the Icariside II (IS) inhibited mTORC1 signaling in sarcoma cells (Figure 3A)
Summary
Sarcomas are mesenchymal malignancies that exhibit a higher percentage of overall cancer morbidity and mortality in children and adolescents than in adults [1]. Sarcoma cells exhibit high rate of glycolysis and mRNA translation [11, 12]. IS inhibited aberrant energy homeostasis evidenced by the reduction of energy production (glycolysis) and energy consumption (mRNA translation) in sarcoma cells. IS inhibited aberrant energy homeostasis through mTORC1-4E-BP1 axis, which contributed to its anti-proliferation effect. MTORC1-4E-BP1 axis regulated the level of c-myc which linked the crosstalk between glycolysis and mRNA translation in IS treated sarcoma cells. This is a novel mechanism of IS to inhibit cell proliferation in sarcoma cells
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