Tankyrase:肿瘤治疗的新靶点

The Role of Tankyrase in Cancer Therapy

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。

Shelterin, including TRF1, TRF2, RAP1, TIN2, TPP1, and POT1, is involved in the functioning of telomeres. Through interactions with some telomere-associated proteins, Shelterin proteins might directly or indirectly regulate the length of the telomere. Among those telomere-associated proteins, tankyrase can poly（ADP-ribosyl）ate TRF1, and release it from the telomere, facilitating telomerase access to the telomere and inducing telomere lengthening. In most cancer cells, telomerase activity was largely upregulated, so in theory, inhibition of telomerase can induce shortening of the telomere and suppress the proliferation of cancer cells. The telomere shortening is a gradual process, and there is a time gap between the inhibition of telomerase activity and the loss of the shortened telomere＇s ability to protect the end of the chromosome. The shortened telomere may induce the efficacy of telomerase inhibition agents. Recent studies have shown that tankyrase is positively correlated with telomerase activity, and tankyrase inhibitors can induce cancer cell apoptosis by in- creasing telomere shortening. However, in some cancer cells relying on the mechanisms of ALT tomaintain telomere length, tankyrase inhibition agents arrest the cancer cell growth by inhibiting the process of mitosis. In addition, the Wnt sig- nal pathway is another target of tankyrase inhibitors, largely because the tankyrase inhibitors can increase axin levels, which, in turn, induce the degradation of β-catenin, and eventually inhibit cancer cell proliferation. Tankyrase inhibitors might have strong anti-cancer abilities, considering the many signal pathways they target. Based on the recent studies of tankyrase, this article mainly focuses on the potential role of tankyrase in cancer therapy.