Bioinspired Soft Matter Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 2005 Songhua Road, Shanghai 200438, China.
Nano Lett. 2021 Jan 13;21(1):747-755. doi: 10.1021/acs.nanolett.0c04435. Epub 2020 Dec 23.
The Yes-associated protein (YAP) is a major oncoprotein responsible for cell proliferation control. YAP's oncogenic activity is regulated by both the Hippo kinase cascade and uniquely by a mechanical-force-induced actin remodeling process. Inspired by reports that ovarian cancer cells specifically accumulate the phosphatase protein ALPP on lipid rafts that physically link to actin cytoskeleton, we developed a molecular self-assembly (MSA) technology that selectively halts cancer cell proliferation by inactivating YAP. We designed a ruthenium-complex-peptide precursor molecule that, upon cleavage of phosphate groups, undergoes self-assembly to form nanostructures specifically on lipid rafts of ovarian cancer cells. The MSAs exert potent, cancer-cell-specific antiproliferative effects in multiple cancer cell lines and in mouse xenograft tumor models. Our work illustrates how basic biochemical insights can be exploited as the basis for a nanobiointerface fabrication technology which links nanoscale protein activities at specific subcellular locations to molecular biological activities to suppress cancer cell proliferation.
Yes 相关蛋白（YAP）是一种主要的癌蛋白，负责控制细胞增殖。YAP 的致癌活性受到 Hippo 激酶级联和独特的机械力诱导的肌动蛋白重塑过程的调节。受卵巢癌细胞特异性地将磷酸酶蛋白 ALPP 积累在与肌动蛋白细胞骨架物理连接的脂筏上的报道的启发，我们开发了一种分子自组装（MSA）技术，通过使 YAP 失活来选择性地阻止癌细胞增殖。我们设计了一种钌配合肽前体分子，在磷酸基团被切割后，会自行组装，专门在卵巢癌细胞的脂筏上形成纳米结构。MSAs 在多种癌细胞系和小鼠异种移植肿瘤模型中发挥强效的、特异性的抗癌增殖作用。我们的工作说明了如何利用基本的生化见解作为纳米生物界面制造技术的基础，该技术将特定亚细胞位置的纳米级蛋白质活性与分子生物学活性联系起来，以抑制癌细胞增殖。
