A Novel ERK2 Degrader Z734 Induces Apoptosis of MCF-7 Cells via the HERC3/p53 Signaling Pathway.
A Novel ERK2 Degrader Z734 Induces Apoptosis of MCF-7 Cells via the HERC3/p53 Signaling Pathway.
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DOI：
10.3390/molecules27144337
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发表时间：
2022-07-06
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乳腺癌是世界范围内的主要死亡原因之一，针对特定蛋白质或各种分子途径的合成化学品（如ERK抑制剂和降解剂）已被深入研究。ERK的靶点参与重要细胞机制的调节，并支持抗癌治疗的进展。在这项研究中，我们确定了一种新的小分子，我们命名为Z734，作为一种新的丝裂原活化蛋白激酶1（ERK 2）降解剂，并证明Z734通过诱导p53介导的人乳腺癌细胞凋亡途径抑制细胞生长。用Z734处理导致癌细胞增殖、集落形成和迁移侵袭的抑制，以及通过凋亡的癌细胞死亡。此外，Co-IP和GST pulldown实验表明，含有E3泛素蛋白连接酶3（HERC 3）的HECT和RLD结构域可以通过HECT结构域直接与ERK 2相互作用，促进ERK 2的泛素化。我们还观察到HERC 3和p53之间对于细胞凋亡的调节的强烈联系。HERC 3可以增加p53的蛋白质和磷酸化水平，这进一步促进凋亡活性。在异种移植小鼠模型中，与单次给药组相比，Z734与拉帕替尼联合给药组获得了该效果。综上所述，我们的研究结果表明，Z734通过凋亡积极控制乳腺癌的发展，HERC 3可能介导ERK 2和p53信号转导，这为临床治疗提供了新的潜在靶点。
Breast cancer is one of the leading causes of death worldwide, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as ERK inhibitors and degraders, have been intensively investigated. The targets of ERK participate in the regulation of critical cellular mechanisms and underpin the progression of anticancer therapy. In this study, we identified a novel small molecule, which we named Z734, as a new mitogen–activated protein kinase 1 (ERK2) degrader and demonstrated that Z734 inhibits cell growth by inducing p53–mediated apoptotic pathways in human breast cancer cells. Treatment with Z734 resulted in the inhibition of cancer cell proliferation, colony formation and migration invasion, as well as cancer cell death via apoptosis. In addition, the Co–IP and GST pulldown assays indicated that the HECT and RLD domains containing E3 ubiquitin protein ligase 3 (HERC3) could directly interact with ERK2 through the HECT domain, promoting ERK2 ubiquitination. We also observed a strong link between HERC3 and p53 for the modulation of apoptosis. HERC3 can increase the protein and phosphorylation levels of p53, which further promotes apoptotic activity. In a xenograft mouse model, the effect was obtained in a treatment group that combined Z734 with lapatinib compared with that of the single–treatment groups. In summary, our results indicated that Z734 actively controls the development of breast cancer through apoptosis, and HERC3 may mediate ERK2 and p53 signaling, which offers new potential targets for clinical therapy.
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