Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Nat Chem Biol. 2017 Sep;13(9):994-1001. doi: 10.1038/nchembio.2442. Epub 2017 Jul 24.
The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC-Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal cancer cells. Our work demonstrates the feasibility of exploiting APC-Asef interaction to regulate the migration of colorectal cancer cells, and provides what to our knowledge is the first class of protein-protein interaction inhibitors available for the development of cancer therapeutics targeting APC-Asef signaling.
腺瘤性结肠息肉病（APC）与受体 Asef 的结合解除了 Asef 的负分子内调节，导致人结直肠癌细胞的异常迁移。由于 APC 和 Asef 之间的相互作用在转移扩散中起着至关重要的作用，因此该相互作用是抗结直肠癌治疗的一个有吸引力的靶点。我们合理设计了一系列拟肽，这些拟肽可作为 APC 界面的有效抑制剂。晶体结构以及生化和细胞测定表明，APC 口袋中的拟肽通过破坏 APC-Asef 相互作用抑制结直肠细胞的迁移。通过将肽模拟抑制剂用作化学探针，我们发现 CDC42 是涉及结直肠癌细胞中 APC 刺激的 Asef 激活的下游 GTPase。我们的工作证明了利用 APC-Asef 相互作用来调节结直肠癌细胞迁移的可行性，并提供了据我们所知的针对 APC-Asef 信号靶向癌症治疗的第一种蛋白质-蛋白质相互作用抑制剂。
