Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma.
Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma.
复制标题
DOI：
10.1158/1535-7163.mct-18-0176
复制
发表时间：
2018-11
影响因子：
5.7
通讯作者：
Wang HG
中科院分区：
文献类型：
--
作者：
Dower CM;Bhat N;Gebru MT;Chen L;Wills CA;Miller BA;Wang HG
神经母细胞瘤是儿童人群中最常见的颅外恶性肿瘤，占儿童所有癌症相关死亡的9%以上。自噬是一种促进肿瘤细胞生长和存活的细胞自我保护机制，使其成为治疗癌症的有吸引力的靶点。然而，自噬在神经母细胞瘤肿瘤生长和转移中的作用在很大程度上是不确定的。在这里，我们证明了用最近开发的ULK 1小分子抑制剂SBI-0206965靶向抑制必需的自噬激酶unc-51样自噬激酶1（ULK 1），可显著降低SK-N-AS，SH-SY 5 Y和SK-N-DZ神经母细胞瘤细胞系的细胞生长并促进细胞凋亡。此外，ULK 1的显性阴性突变体（dnULK 1 K46 N）对ULK 1的抑制显著降低了携带SK-N-AS异种移植肿瘤的小鼠的生长和转移性疾病以及存活率。我们还表明，SBI-0206965使SK-N-AS细胞对TRAIL治疗敏感，但对mTOR抑制剂（INK 128，Torin 1）或拓扑异构酶抑制剂（多柔比星，拓扑替康）不敏感。总的来说，这些发现表明ULK 1是一个可行的药物靶点，并表明ULK 1抑制剂可能为神经母细胞瘤的治疗提供一种新的治疗选择。
Neuroblastoma is the most common extracranial malignancy in the pediatric population, accounting for over 9% of all cancer-related deaths in children. Autophagy is a cell self-protective mechanism that promotes tumor cell growth and survival, making it an attractive target for treating cancer. However, the role of autophagy in neuroblastoma tumor growth and metastasis is largely undefined. Here we demonstrate that targeted inhibition of an essential autophagy kinase, unc-51 like autophagy kinase 1 (ULK1), with a recently developed small molecular inhibitor of ULK1, SBI-0206965, significantly reduces cell growth and promotes apoptosis in SK-N-AS, SH-SY5Y, and SK-N-DZ neuroblastoma cell lines. Furthermore, inhibition of ULK1 by a dominant-negative mutant of ULK1 (dnULK1K46N) significantly reduces growth and metastatic disease and prolongs survival of mice bearing SK-N-AS xenograft tumors. We also show that SBI-0206965 sensitizes SK-N-AS cells to TRAIL treatment, but not to mTOR inhibitors (INK128, Torin1) or topoisomerase inhibitors (doxorubicin, topotecan). Collectively, these findings demonstrate that ULK1 is a viable drug target and suggest that inhibitors of ULK1 may provide a novel therapeutic option for the treatment of neuroblastoma.