Signal Transduction Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Rep. 2012 Apr 19;1(4):309-16. doi: 10.1016/j.celrep.2012.02.006. Epub 2012 Mar 19.
Inhibition of NEDD8-activating enzyme (NAE) has emerged as a highly promising approach to treat cancer through the adenosine sulfamate analog MLN4924. Here, we show that selective pressure results in HCT116 colorectal carcinoma cells with decreased MLN4924 sensitivity and identify a single-nucleotide transition that changes alanine 171 to threonine (A171T) of the NAE subunit UBA3. This reduces the enzyme's affinity for MLN4924 and ATP while increasing NEDD8 activation at physiological ATP concentrations. Expression of UBA3 A171T is sufficient to decrease MLN4924 sensitivity of naive HCT116 cells, indicating that it is a dominant suppressor of MLN4924-mediated cell death. Our data suggest that the on-target potency of MLN4924 selects for a point mutation in NAE that overcomes the molecule's inhibitory effects, allowing cancer cell survival.
NEDD8-激活酶（NAE）的抑制已成为通过腺苷磺酸盐类似物 MLN4924 治疗癌症的一种极具前景的方法。在这里，我们表明，选择性压力导致 HCT116 结直肠癌细胞对 MLN4924 的敏感性降低，并鉴定出一个单核苷酸转换，将 NAE 亚基 UBA3 的丙氨酸 171 变为苏氨酸（A171T）。这降低了酶对 MLN4924 和 ATP 的亲和力，同时在生理 ATP 浓度下增加了 NEDD8 的激活。UBA3 A171T 的表达足以降低未处理的 HCT116 细胞对 MLN4924 的敏感性，表明它是 MLN4924 介导的细胞死亡的显性抑制子。我们的数据表明，MLN4924 的靶标效力选择了 NAE 中的一个点突变，该突变克服了该分子的抑制作用，从而允许癌细胞存活。
