NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells.
NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells.
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DOI：
10.1158/0008-5472.can-10-2062
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Dutta A
中科院分区：
文献类型：
--
作者：
Lin JJ;Milhollen MA;Smith PG;Narayanan U;Dutta A
MLN 4924是一种一流的实验性抗癌药物，可抑制NEDD 8活化酶，从而抑制cullin-RING E3泛素连接酶并稳定许多cullin底物。MLN 4924抑制癌细胞增殖的机制尚未确定，尽管它伴随着DNA再复制和伴随的DNA损伤。在此，我们证明了DNA复制因子Cdt 1（Cullin 1和4的底物）的稳定性对于MLN 4924触发DNA再复制和抑制细胞增殖至关重要。发现即使仅暴露于MLN 4924 1小时（足以升高Cdt 1 4-5小时）也足以诱导DNA再复制并激活细胞凋亡和衰老途径。处于S期的细胞最敏感，表明MLN 4924对高度增殖的癌症毒性最大。尽管MLN 4924诱导的细胞衰老似乎依赖于p53及其下游效应物p21 Waf 1的诱导，但我们发现p53−/−和p21−/−细胞甚至比野生型细胞对MLN 4924更敏感。我们的结果表明，细胞凋亡，而不是衰老，可能是MLN 4924的抗增殖作用更重要。此外，我们的研究结果表明，短暂暴露于这种新的研究药物应该有助于控制p53阴性癌细胞，这通常会带来重大的临床挑战。
MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA re-replication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of Cullins 1 and 4, is critical for MLN4924 to trigger DNA re-replication and inhibit cell proliferation. Even only one hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4–5 hours, was found to be sufficient to induce DNA re-replication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence appears to be dependent on induction of p53 and its downstream effector p21Waf1, we found that p53−/−and p21−/− cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, may be more important for the anti-proliferative effect of MLN4924. Further, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.