NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivo
NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivo
复制标题
NG25 是一种新型 TAK1 抑制剂，可在体外和体内抑制 KRAS 突变结直肠癌的生长
DOI：
10.1007/s10495-018-1498-z
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发表时间：
2019-02-01
期刊：
影响因子：
7.2
通讯作者：
Wang, Yufang
中科院分区：
文献类型：
--
作者：
Ma, Qizhao;Gu, Ling;Wang, Yufang
KRAS 突变是结直肠癌 (CRC) 中最常见的基因改变之一。尽管直接靶向 KRAS 仍然是抗癌治疗中的一个挑战，但替代性抑制 KRAS 相关信号通路已经被有效地解决。在此，我们首次报道了 MAP 激酶，即转化生长因子-β 激活激酶 1 (TAK1)，通常在 CRC 细胞系中表达，并与 KRAS 突变状态显着相关。小分子抑制剂 NG25 抑制 TAK1 可以在体外和体内抑制 CRC 细胞增殖，尤其是 KRAS 突变细胞。 NG25 通过调节 B 细胞淋巴瘤-2 (Bcl-2) 家族和凋亡蛋白抑制剂 (IAP) 家族，在 KRAS 突变细胞和原位 CRC 小鼠模型中诱导 caspase 依赖性细胞凋亡。除了抑制 MAPK 下游分子（包括 ERK、JNK 和 p38 磷酸化）外，NG25 还可以阻断 KRAS 突变细胞中 NF-κB 的激活。作为 NF-κB 的靶基因，XIAP 表达下调可能不仅参与 NG25 诱导的细胞凋亡，而且还减少了可激活 TAK1 下游信号通路的 TAK1-XIAP 复合物的形成，形成正反馈环，进一步诱导 KRAS 突变的 CRC 细胞凋亡。总之，这些发现表明 TAK1 是携带 KRAS 突变的 CRC 存活的重要激酶，而 NG25 可能是 KRAS 突变 CRC 的潜在治疗策略。
KRAS mutations are one of the most prevalent genetic alterations in colorectal cancer (CRC). Although directly targeting KRAS still is a challenge in anti-cancer therapies, alternatively inhibiting KRAS related signaling pathways has been approached effectively. Here we firstly reported that MAP kinase, transforming growth factor-β-activated kinase 1 (TAK1), commonly expressed in CRC cell lines and significantly associated with KRAS mutation status. Inhibition of TAK1 by the small molecular inhibitor NG25 could inhibit CRC cells proliferation in vitro and in vivo, especially in KRAS-mutant cells. NG25 induced caspase-dependent apoptosis in KRAS-mutant cells and in orthotopic CRC mouse models by regulating the B-cell lymphoma-2 (Bcl-2) family and the inhibitor of apoptosis protein (IAP) family. Besides inhibiting molecules downstream of MAPK, including ERK, JNK and p38 phosphorylation, NG25 could block NF-κB activation in KRAS-mutant cells. As a target gene of NF-κB, down-regulated XIAP expression may be not only involved in apoptosis induced by NG25, but also reducing the formation of TAK1-XIAP complex that can activate TAK1 downstream signaling pathways, which forms a positive feedback loop to further induce apoptosis in KRAS-mutant CRC cells. Together, these findings indicated that TAK1 is an important kinase for survival of CRCs harboring KRAS mutations, and that NG25 may be a potential therapeutic strategy for KRAS-mutant CRC.