State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Proteomics Laboratory, Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing, 100191, China.
Cell Death Dis. 2021 May 14;12(5):492. doi: 10.1038/s41419-021-03780-y.
Syndecan-4 (SDC4) functions as a major endogenous membrane-associated receptor and widely regulates cytoskeleton, cell adhesion, and cell migration in human tumorigenesis and development, which represents a charming anti-cancer therapeutic target. Here, SDC4 was identified as a direct cellular target of small-molecule bufalin with anti-hepatocellular carcinoma (HCC) activity. Mechanism studies revealed that bufalin directly bond to SDC4 and selectively increased SDC4 interaction with substrate protein DEAD-box helicase 23 (DDX23) to induce HCC genomic instability. Meanwhile, pharmacological promotion of SDC4/DDX23 complex formation also inactivated matrix metalloproteinases (MMPs) and augmented p38/JNK MAPKs phosphorylation, which are highly associated with HCC proliferation and migration. Notably, specific knockdown of SDC4 or DDX23 markedly abolished bufalin-dependent inhibition of HCC proliferation and migration, indicating SDC4/DDX23 signaling axis is highly involved in the HCC process. Our results indicate that membrane-spanning proteoglycan SDC4 is a promising druggable target for HCC, and pharmacological regulation of SDC4/DDX23 signaling axis with small-molecule holds great potential to benefit HCC patients.
硫酸乙酰肝素蛋白聚糖 4（SDC4）作为主要的内源性膜相关受体，广泛调节人类肿瘤发生和发展中的细胞骨架、细胞黏附和细胞迁移，是一个很有吸引力的抗癌治疗靶点。在这里，SDC4 被鉴定为具有抗肝癌（HCC）活性的小分子蟾毒灵的直接细胞靶标。机制研究表明，蟾毒灵直接与 SDC4 结合，并选择性地增加 SDC4 与底物蛋白 DEAD 盒解旋酶 23（DDX23）的相互作用，导致 HCC 基因组不稳定性。同时，药理学促进 SDC4/DDX23 复合物的形成也使基质金属蛋白酶（MMPs）失活，并增强 p38/JNK MAPKs 的磷酸化，这与 HCC 的增殖和迁移高度相关。值得注意的是，SDC4 或 DDX23 的特异性敲低显著消除了蟾毒灵依赖的 HCC 增殖和迁移抑制，表明 SDC4/DDX23 信号轴高度参与 HCC 过程。我们的研究结果表明，跨膜糖蛋白 SDC4 是 HCC 的一个有前途的可药物治疗靶点，用小分子调节 SDC4/DDX23 信号轴具有很大的潜力使 HCC 患者受益。
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