Oleuropein is a natural inhibitor of PAI-1-mediated proliferation in human ER-/PR- breast cancer cells.

Autor: Tzekaki EE; Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece., Geromichalos G; Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece., Lavrentiadou SN; School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece., Tsantarliotou MP; School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece., Pantazaki AA; Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece., Papaspyropoulos A; Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece. apapaspyropoulos@chem.auth.gr.
Jazyk: angličtina
Zdroj: Breast cancer research and treatment [Breast Cancer Res Treat] 2021 Apr; Vol. 186 (2), pp. 305-316. Date of Electronic Publication: 2021 Jan 03.
DOI: 10.1007/s10549-020-06054-x
Abstrakt: Purpose: Elevated expression of PAI-1 has been widely linked with adverse outcomes in a variety of human cancers, such as breast, gastric and ovarian cancers, rendering PAI-1 a prognostic biomarker. As a result, several chemical inhibitors are currently being developed against PAI-1; however, the clinical setting where they might confer survival benefits has not yet been elucidated.
Methods: RNA sequencing data analysis from the TCGA/GTEx cancer portals (n = 3607 samples). In silico molecular docking analyses to predict functional macromolecule interactions. ER-/PR- (MDA-MB-231) and ER+/PR+ (MCF-7) breast cancer cell lines implemented to assess the effect of oleuropein as a natural inhibitor of PAI-1-mediated oncogenic proliferation.
Results: We show that high PAI-1 levels inversely correlate with ER and PR expressions in a wide panel of estrogen/progesterone-responsive human malignancies. By implementing an in silico molecular docking analysis, we identify oleuropein, a phenolic component of olive oil, as a potent PAI-1-binding molecule displaying increased affinity compared to the other olive oil constituents. We demonstrate that EVOO or oleuropein treatment alone may act as a natural PAI-1 inhibitor by incrementally destabilising PAI-1 levels selectively in ER-/PR- breast cancer cells, accompanied by downstream caspase activation and cell growth inhibition. In contrast, ER+/PR+ breast cancer cells, where PAI-1 expression is absent or low, do not adequately respond to treatment.
Conclusions: Our study demonstrates an inverse correlation between PAI-1 and ESR1/PGR levels, as well as overall patient survival in estrogen/progesterone-responsive human tumours. With a focus on breast cancer, our data identify oleuropein as a natural PAI-1 inhibitor and suggest that oleuropein-mediated PAI-1 destabilisation may confer clinical benefit only in ER-/PR- tumours.
Databáze: MEDLINE
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