Perta Nunzio, Torrieri Di Tullio Laura, Cugini Elisa, Fattibene Paola, Rapanotti Maria Cristina, Borromeo Ilaria, Forni Cinzia, Malaspina Patrizia, Cacciamani Tiziana, Di Marino Daniele, Rossi Luisa, De Luca Anastasia
Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy.
New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy.
Biology (Basel). 2023 Nov 16;12(11):1437. doi: 10.3390/biology12111437.
Polyphenols have gained increasing attention for their therapeutic potential, particularly in conditions like cancer, due to their established antioxidant and anti-inflammatory properties. Recent research highlights their ability to bind to transition metals, such as copper. This is particularly noteworthy given the key role of copper both in the initiation and progression of cancer. Copper can modulate the activity of kinases required for the epithelial-mesenchymal transition (EMT), a process fundamental to tumor cell dissemination. We have previously demonstrated the copper-binding capacity of oleuropein, a secoiridoid found in . In the present study, we investigated the effect of hydroxytyrosol, the primary oleuropein metabolite, on the metastatic potential of three triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468, and SUM159). We found that hydroxytyrosol modulated the intracellular copper levels, influencing both the epithelial and mesenchymal markers, by downregulating copper-dependent AKT phosphorylation, a member of the EMT signaling cascade, through Western blot, RT-qPCR, and immunofluorescence. Indeed, by optical spectra, EPR, and in silico approaches, we found that hydroxytyrosol formed a complex with copper, acting as a chelating agent, thus regulating its homeostasis and affecting the copper-dependent signaling cascades. While our results bring to light the copper-chelating properties of hydroxytyrosol capable of countering tumor progression, they also provide further confirmation of the key role of copper in promoting the aggressiveness of triple-negative breast cancer cells.
由于其已确定的抗氧化和抗炎特性，多酚因其治疗潜力而受到越来越多的关注，尤其是在癌症等疾病中。最近的研究突出了它们与过渡金属（如铜）结合的能力。鉴于铜在癌症的发生和发展中都起着关键作用，这一点尤其值得注意。铜可以调节上皮-间质转化（EMT）所需激酶的活性，EMT是肿瘤细胞扩散的一个基本过程。我们之前已经证明了橄榄苦苷的铜结合能力，橄榄苦苷是一种在……中发现的裂环环烯醚萜。在本研究中，我们研究了橄榄苦苷的主要代谢产物羟基酪醇对三种三阴性乳腺癌细胞系（MDA-MB-231、MDA-MB-468和SUM159）转移潜能的影响。我们发现，羟基酪醇通过蛋白质免疫印迹法、逆转录-定量聚合酶链反应和免疫荧光法下调EMT信号级联成员铜依赖性AKT磷酸化，从而调节细胞内铜水平，影响上皮和间质标志物。事实上，通过光谱、电子顺磁共振和计算机模拟方法，我们发现羟基酪醇与铜形成了一种复合物，作为一种螯合剂，从而调节其体内平衡并影响铜依赖性信号级联。虽然我们的结果揭示了羟基酪醇能够对抗肿瘤进展的铜螯合特性，但它们也进一步证实了铜在促进三阴性乳腺癌细胞侵袭性方面的关键作用。
