Downregulation of uridine-cytidine kinase like-1 decreases proliferation and enhances tumor susceptibility to lysis by apoptotic agents and natural killer cells
Downregulation of uridine-cytidine kinase like-1 decreases proliferation and enhances tumor susceptibility to lysis by apoptotic agents and natural killer cells
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DOI：
10.1007/s10495-009-0385-z
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发表时间：
2009-10-01
期刊：
影响因子：
7.2
通讯作者：
Kornbluth, Jacki
中科院分区：
文献类型：
--
作者：
Ambrose, Elise C.;Kornbluth, Jacki
自然杀伤（NK）细胞通过直接抗肿瘤细胞毒性靶向并杀死肿瘤细胞。NK细胞溶解相关分子（NKLAM）是参与这种细胞溶解功能的蛋白质。作为E3泛素连接酶，NKLAM结合并泛素化一种新的蛋白质，尿苷-胞苷激酶样-1（UCKL-1），靶向其降解。然而，UCKL-1在肿瘤细胞存活和NK细胞毒性中的功能尚不清楚。UCKL-1与尿苷激酶的同源性和在肿瘤细胞中的过表达表明UCKL-1在肿瘤生长和/或存活中的作用。我们提出NKLAM和UCKL-1在肿瘤细胞中相互作用，其中UCKL-1的降解导致肿瘤细胞凋亡增加。在此，我们使用RNA干扰下调K562红白血病细胞中UCKL-1的表达。可以看出，下调UCKL-1启动了细胞凋亡并减慢了细胞周期，导致小干扰UCKL-1 RNA处理的K562细胞培养物中生长较低。此外，与对照相比，化学治疗剂星形孢菌素被认为在UCKL-1耗尽的K562细胞中通过凋亡诱导细胞死亡方面更有效。我们还发现UCKL-1缺失的K562细胞比对照组更容易受到NK介导的细胞溶解。这些结果表明UCKL-1在肿瘤细胞存活中的作用，并表明UCKL-1抑制剂在癌症治疗中的可能治疗潜力。
Natural killer (NK) cells target and kill tumor cells by direct anti-tumor cytotoxicity. NK lytic-associated molecule (NKLAM) is a protein involved in this cytolytic function. Acting as an E3 ubiquitin ligase, NKLAM binds to and ubiquitinates a novel protein, uridine-cytidine kinase like-1 (UCKL-1), targeting it for degradation. However, UCKL-1's function in tumor cell survival and NK cell cytotoxicity is unknown. UCKL-1's homology to uridine kinases and over expression in tumor cells suggests a role for UCKL-1 in tumor growth and/or survival. We propose that NKLAM and UCKL-1 interact in the tumor cell, where degradation of UCKL-1 leads to increased tumor cell apoptosis. Here we use RNA interference to downregulate UCKL-1 expression in K562 erythroleukemia cells. It was seen that downregulation of UCKL-1 initiated apoptosis and slowed the cell cycle, resulting in lower growth in the small interfering UCKL-1 RNA treated K562 cell culture. In addition, the chemotherapeutic agent staurosporine was seen to be more effective in inducing cell death by apoptosis in UCKL-1 depleted K562 cells compared with controls. We also found that UCKL-1 depleted K562 cells were more susceptible to NK mediated cytolysis than controls. These results indicate a role for UCKL-1 in tumor cell survival and suggest possible therapeutic potential of UCKL-1 inhibitors in cancer treatment.