Quantitative proteomics discloses monacolin K-induced alterations in triple-negative breast cancer cell proteomes and phosphoproteomes

摘要

A positive prognosis of triple-negative breast cancer can be considered as one of the major challengesin clinical studies; accordingly, scientific research has the mission to find out novel chemotherapeuticsto make it curable. In recent times, a good potential of dietary bioactive natural substances, callednutraceuticals, in suppressing cancer cell proliferation via gene expression regulation has beendiscovered: this effect and the lack of toxicity make nutraceuticals potentially effective agents againstcancers. Monacolin K from red rice, a FDA-approved and well-tolerated compound generally employedto treat hypercholesterolemia, has been proved to have anti-proliferative and apoptotic effects in a widepanel of triple-negative breast cancers. Thus, an unbiased analysis of monacolin K-induced MDA-MB-231 cellular pathway alterations has been carried out by quantitative proteomics exploiting isobaric tags.Despite the positive modulation of some proteins already reported in the literature, an increasedconcentration of the tissue-type plasminogen activator PLAT has interestingly been found. This is amarker of good prognosis in mammary cancer, suggesting the anti-metastatic properties of this moleculeas strongly associated with the alterations in the cytoskeleton organization and the consequentmodulation of adhesion, motility and proteolysis. In accordance, some of the found monacolinK-induced phosphoproteome alterations have a tight connection to cell migration mechanisms. In thissetting, the over-phosphorylation of Lamin A and of melanophilin induced by monacolin K has beenvery attractive. Moreover, monacolin K exerts its effect on the over-expression of the tissue inhibitormetalloproteinase-2 (TIMP-2), an endogenous metalloproteinase inhibitor. This protein modulatesgrowth, migration and invasion of tumor cells and inhibits tumor angiogenesis.