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由TRF1、TRF2、RAP1、TIN2、TPP1和POT1蛋白组成的shelterin端粒蛋白网络参与维持端粒的正常功能。其中Tankyrase可核糖基化TRF1,使其与端粒解离,并导致端粒酶与端粒的结合,从而维持端粒长度的相对恒定。多数肿瘤细胞中端粒酶活性升高,因而端粒酶抑制剂可特异诱导端粒的缩短而抑制肿瘤细胞生长。但端粒缩短是一渐进过程,在端粒酶活性受到抑制直至缩短的端粒丧失其染色体末端保护功能时会有一段时间间隔。因此,端粒的缩短也会降低端粒酶抑制剂的药效。Tankyrase与端粒酶活性升高呈正相关,因而Tankyrase抑制剂可诱导端粒的缩短,进而诱导肿瘤细胞凋亡。在少数以ALT机制维持端粒长度相对恒定的肿瘤细胞中,Tankyrase抑制剂则通过抑制细胞的有丝分裂诱导肿瘤细胞的生长阻滞。此外,Tankyrase抑制剂增强Wnt信号途径中轴蛋白的表达水平,诱导β-连环蛋白的降解,从而抑制肿瘤细胞增殖。由于Tankyrase抑制剂可通过多种途径拮抗肿瘤细胞的生长,因而其表现出光谱的抗肿瘤活性。本文就Tankyrase在肿瘤治疗中的研究进展作一综述。
The shelterin telomere network, composed of the TRF1, TRF2, RAP1, TIN2, TPP1 and POT1 proteins, is involved in the maintenance of telomere normal function. Tankyrase, which ribosylates TRF1, dissociates from telomeres and results in the binding of telomerase to telomeres, thereby maintaining a relatively constant telomere length. Telomerase activity is elevated in most tumor cells, so telomerase inhibitors can specifically induce telomere shortening and inhibit tumor cell growth. However, telomere shortening is a gradual process, with some time lagging until telomerase activity is inhibited until the shortened telomeres lose their terminal protection of the chromosome. Therefore, telomere shortening also reduces the efficacy of telomerase inhibitors. Tankyrase and telomerase activity was positively correlated, so Tankyrase inhibitors can induce telomere shortening, thereby inducing tumor cell apoptosis. In a few tumor cells that maintain a relatively constant telomere length with ALT, Tankyrase inhibitors induce tumor cell growth arrest by inhibiting cell mitosis. In addition, Tankyrase inhibitors enhance the expression of axonal proteins in the Wnt signaling pathway, induce the degradation of β-catenin and thereby inhibit tumor cell proliferation. Since Tankyrase inhibitors can antagonize the growth of tumor cells in a variety of ways, they exhibit spectrally anti-tumor activity. This article reviews the progress of Tankyrase in the treatment of cancer.