Le Xiao-Feng, Pruefer Franz, Bast Robert C
Department of Experimental Therapeutics, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Cell Cycle. 2005 Jan;4(1):87-95. doi: 10.4161/cc.4.1.1360. Epub 2005 Jan 10.
Anti-HER2 antibody trastuzumab is emerging as a frontline therapy for patients with metastatic breast cancers that overexpress HER2. Understanding the molecular mechanisms by which the antibody inhibits tumor growth should permit the design of even more effective trastuzumab-based protocols. Several groups including our own have demonstrated that induction of cyclin-dependent kinase (CDK) inhibitor p27Kip1 protein is one of the key mechanisms of action of HER2-targeting antibodies. In this review, we discuss currently available data regarding the multiple signaling targets and pathways by which HER2-targeting antibodies upregulate p27Kip1 protein in breast cancer cells that overexpress HER2. Anti-HER2 antibodies inhibit HER2-mediated signaling in cancer cells, ultimately upregulating the levels and activity of p27Kip1 protein. At least six signaling targets and pathways are modulated by trastuzumab. By inhibiting CDK2 and decreasing Thr187 phosphorylation of p27Kip1, trastuzumab abrogates targeting of SCF-ubiquitin E3 ligase and minimizes proteasome degradation of p27Kip1. By inhibiting AKT and human kinase interacting stathmin (hKIS), trastuzumab blocks Thr157-, Thr198- and Ser10-induced p27Kip1 translocation from the nucleus to the cytosol, which increases the inhibitory effect of p27Kip1. By inhibiting Jun activation domain-binding protein 1 (Jab1) trastuzumab increases nuclear retention of p27Kip1. By inhibiting cyclin D and c-Myc, trastuzumab releases the sequestrated p27bKip1 protein from cyclin D-CDK4/6 complexes and increase the effect of p27Kip1 on CDK2-cyclin E complexes. By stimulating minibrain related kinase (MIRK), trastuzumab stabilizes p27Kip1 in the nucleus, which increases inhibitory action of p27Kip1 on CDK2. The targets and pathways affected by trastuzumab work in concert to maximize the expression and inhibitory effect of p27Kip1, which leads to cell cycle G1 arrest and growth inhibition.
抗HER2抗体曲妥珠单抗正成为HER2过表达转移性乳腺癌患者的一线治疗药物。了解该抗体抑制肿瘤生长的分子机制有助于设计出更有效的基于曲妥珠单抗的治疗方案。包括我们在内的多个研究小组已证明，细胞周期蛋白依赖性激酶（CDK）抑制剂p27Kip1蛋白的诱导是HER2靶向抗体的关键作用机制之一。在本综述中，我们讨论了目前有关HER2靶向抗体在HER2过表达乳腺癌细胞中上调p27Kip1蛋白的多个信号靶点和途径的可用数据。抗HER2抗体抑制癌细胞中HER2介导的信号传导，最终上调p27Kip1蛋白的水平和活性。曲妥珠单抗至少调节六个信号靶点和途径。通过抑制CDK2并减少p27Kip1的Thr187磷酸化，曲妥珠单抗消除了SCF泛素E3连接酶的靶向作用，并使p27Kip1的蛋白酶体降解降至最低。通过抑制AKT和人激酶相互作用的微管相关蛋白（hKIS），曲妥珠单抗阻断了Thr157、Thr198和Ser10诱导的p27Kip1从细胞核到细胞质的易位，从而增强了p27Kip1的抑制作用。通过抑制Jun激活域结合蛋白1（Jab1），曲妥珠单抗增加了p27Kip1在细胞核中的保留。通过抑制细胞周期蛋白D和c-Myc，曲妥珠单抗从细胞周期蛋白D-CDK4/6复合物中释放出被隔离的p27bKip1蛋白，并增强了p27Kip1对CDK2-细胞周期蛋白E复合物的作用。通过刺激小脑相关激酶（MIRK），曲妥珠单抗使p27Kip1在细胞核中稳定，从而增强了p27Kip1对CDK2的抑制作用。曲妥珠单抗影响的靶点和途径协同作用，以最大限度地提高p27Kip1的表达和抑制作用，从而导致细胞周期G1期停滞和生长抑制。
