Abstract
Silibinin is a nontoxic flavonoid reported to have anticancer properties. In this study, we show that silibinin exhibits antiproliferative activity on MCF-7 breast cancer cells. Exposure to silibinin leads to a concentration-dependent decrease in global protein synthesis associated with reduced levels of eukaryotic initiation factor 4F complex. Moreover, polysome profile analysis of silibinin-treated cells shows a decrease in polysome content and translation of cyclin D1 mRNA. Silibinin exerts its effects on translation initiation by inhibiting the mammalian target of rapamycin signaling pathway by acting upstream of TSC2. Our results show that silibinin blocks mammalian target of rapamycin signaling with a concomitant reduction in translation initiation, thus providing a possible molecular mechanism of how silibinin can inhibit growth of transformed cells.
Highlights
Deregulated protein synthesis is emerging as a key event in human oncogenesis
Our results indicate that silibinin exhibits antiproliferative activity against MCF-7 human breast cancer cells by inhibiting translation initiation
A partial collapse of polysomes was observed in silibinin-treated cells (Fig. 2C) and was accompanied by more pronounced consequences on the translation of specific mRNAs as we have shown for cyclin D1 (Fig. 2D)
Summary
Regulation of mRNA translation is required for cell growth, proliferation, differentiation, and cellular homeostasis [1, 2]. The recruitment of ribosomes to the 5′-end of mRNAs during translation initiation in eukaryotes is generally thought to be the rate-limiting step of protein synthesis and is under regulation of the mammalian target of rapamycin (mTOR) protein kinase. Cap-dependent translation initiation is stimulated by eukaryotic initiation factor (eIF) 4F, a complex consisting of three subunits: eIF4E, which interacts directly with the mRNA cap structure; eIF4A, a RNA helicase that prepares the mRNA template for ribosome binding; and eIF4G, a large molecular scaffold. Grant support: Canadian Institutes of Health Research operating grant MOP-11354 and Canadian Breast Cancer Research Alliance Translational Acceleration grant 16512.
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