Prill Monika, Sardão Vilma A, Sobczak Mateusz, Nowis Dominika, Szymanski Jedrzej, Wieckowski Mariusz R
Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland.
Cellular Immunotherapy Center, Warsaw University of Life Sciences, 02-787 Warsaw, Poland.
Cancers (Basel). 2024 Sep 28;16(19):3324. doi: 10.3390/cancers16193324.
This work presents a comprehensive evaluation of the role of p66Shc protein in mitochondrial physiology in MDA-MB-231 breast cancer cells. The use of human breast cancer cell line MDA-MB-231 and its genetically modified clones (obtained with the use of the CRISPR-Cas9 technique), expressing different levels of p66Shc protein, allowed us to demonstrate how the p66Shc protein affects mitochondrial metabolism of human breast cancer cells. Changes in the level of p66Shc (its overexpression, and overexpressing of its Serine 36-mutated version, as well as the knockout of p66Shc) exert different effects in breast cancer cells. Interestingly, knocking out p66Shc caused significant changes observed mostly in mitochondrial bioenergetic parameters. We have shown that an MDA-MB-231 (which is a strong metastatic type of breast cancer) clone lacking p66Shc protein is characterized by a significant shift in the metabolic phenotype in comparison to other MDA-MB-231 clones. Additionally, this clone is significantly more vulnerable to doxorubicin treatment. We have proved that p66Shc adaptor protein in human breast cancer cells may exert a different role than in noncancerous cells (e.g., fibroblasts).
这项工作全面评估了p66Shc蛋白在MDA-MB-231乳腺癌细胞线粒体生理学中的作用。使用人乳腺癌细胞系MDA-MB-231及其基因修饰克隆（通过CRISPR-Cas9技术获得），这些克隆表达不同水平的p66Shc蛋白，使我们能够证明p66Shc蛋白如何影响人乳腺癌细胞的线粒体代谢。p66Shc水平的变化（其过表达、丝氨酸36突变版本的过表达以及p66Shc的敲除）在乳腺癌细胞中产生不同的影响。有趣的是，敲除p66Shc导致主要在线粒体生物能量参数中观察到显著变化。我们已经表明，与其他MDA-MB-231克隆相比，缺乏p66Shc蛋白的MDA-MB-231（一种强转移性乳腺癌类型）克隆的代谢表型发生了显著转变。此外，该克隆对多柔比星治疗明显更敏感。我们已经证明，人乳腺癌细胞中的p66Shc衔接蛋白可能发挥与非癌细胞（如成纤维细胞）不同的作用。
