Zhang Bei, Chen Yan, Chen Xinqi, Ren Zhiyao, Xiang Hong, Mao Lipeng, Zhu Guodong
Institute of Gerontology, Guangzhou Geriatric Hospital, Guangzhou Medical University, Guangzhou, China.
State Key Laboratory of Respiratory Disease, Guangzhou Geriatric Hospital, Guangzhou Medical University, Guangzhou, China.
Cancer Cell Int. 2024 Feb 24;24(1):83. doi: 10.1186/s12935-024-03233-4.
Apatinib was the first anti-angiogenic agent approved for treatment of metastatic gastric cancer (GC). However, the emergence of resistance was inevitable. Thus investigating new and valuable off-target effect of apatinib directly against cancer cells is of great significance. Here, we identified extra spindle pole bodies-like 1 (ESPL1) was responsible for apatinib resistance in GC cells through CRISPR genome-wide gain-of-function screening. Loss of function studies further showed that ESPL1 inhibition suppressed cell proliferation, migration and promoted apoptosis in vitro, and accordingly ESPL1 knockdown sensitized GC cells to apatinib. In addition, we found ESPL1 interacted with mouse double minute 2 (MDM2), a E3 ubiquitin protein ligase, and the combination of MDM2 siRNA with apatinib synergistically ameliorated the resistance induced by ESPL1 overexpression. In summary, our study indicated that ESPL1 played a critical role in apatinib resistance in GC cells. Inhibition of MDM2 could rescue the sensitivity of GC cells to apatinib and reverse ESPL1-mediated resistance.
阿帕替尼是首个被批准用于治疗转移性胃癌（GC）的抗血管生成药物。然而，耐药性的出现不可避免。因此，研究阿帕替尼直接作用于癌细胞的新的有价值的脱靶效应具有重要意义。在此，我们通过CRISPR全基因组功能获得性筛选确定了额外纺锤极体样1（ESPL1）是GC细胞中阿帕替尼耐药的原因。功能缺失研究进一步表明，ESPL1抑制在体外抑制细胞增殖、迁移并促进细胞凋亡，因此ESPL1敲低使GC细胞对阿帕替尼敏感。此外，我们发现ESPL1与E3泛素蛋白连接酶小鼠双微体2（MDM2）相互作用，并且MDM2 siRNA与阿帕替尼联合使用可协同改善ESPL1过表达诱导的耐药性。总之，我们的研究表明ESPL1在GC细胞的阿帕替尼耐药中起关键作用。抑制MDM2可恢复GC细胞对阿帕替尼的敏感性并逆转ESPL1介导的耐药性。
