High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.
Institute of Physical Science and Information Technology, Anhui University, Hefei, China.
FEBS Open Bio. 2020 Nov;10(11):2452-2463. doi: 10.1002/2211-5463.13000. Epub 2020 Oct 26.
Certain tumors are dependent on autophagy for survival; thus, the use of unc-51-like autophagy activating kinase (ULK) 1 inhibitors to block autophagy has the potential for tumor treatment. However, ULK1 inhibitors affect processes other than autophagy. Herein, we report that the ULK1 inhibitors SBI-0206965/MRT68921 not only inhibit phosphorylation of histone H3 (Ser10) and delay chromatin condensation but also induce spindle microtubule disorganization to form short and fragmented microtubule polymers. Although the delay in chromatin condensation also delayed mitotic entry, the disorganized microtubule polymers resulted in unsegregated chromosomes and polyploidy. Although the effect on mitotic entry was moderate, polyploidy formation was decreased in ULK1 knockout cells with or without ULK2 knockdown. In conclusion, it will be helpful to consider the roles of ULK1 inhibitors in mitotic dysregulation, as well as autophagy, when evaluating their antitumor efficacy.
某些肿瘤依赖自噬存活；因此，使用 UNC-51 样自噬激活激酶 (ULK)1 抑制剂来阻断自噬有可能用于肿瘤治疗。然而，ULK1 抑制剂除了自噬之外还会影响其他过程。在此，我们报告 ULK1 抑制剂 SBI-0206965/MRT68921 不仅抑制组蛋白 H3 (Ser10)的磷酸化并延迟染色质凝聚，而且还诱导纺锤体微管解聚形成短的和碎片化的微管聚合物。尽管染色质凝聚的延迟也延迟了有丝分裂进入，但解聚的微管聚合物导致染色体未分离和多倍体形成。尽管对有丝分裂进入的影响是中度的，但在 ULK1 敲除细胞中，无论是否敲低 ULK2，多倍体的形成都会减少。总之，在评估其抗肿瘤功效时，考虑 ULK1 抑制剂在有丝分裂失调以及自噬中的作用将是有帮助的。
