SENP1 participates in Irinotecan resistance in human colon cancer cells
SENP1 participates in Irinotecan resistance in human colon cancer cells
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DOI：
10.1002/jcb.29946
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发表时间：
2021-05-26
影响因子：
4
通讯作者：
Huang, Chih-Yang
中科院分区：
文献类型：
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作者：
Chen, Ming-Cheng;Nhan, Do Chi;Huang, Chih-Yang
结直肠癌是世界上最常见的癌症之一。化疗耐药一直是其治疗中遇到的问题。已知SUMO化可以调节蛋白质的稳定性和分解，甚至影响细胞内蛋白质的转位和翻译后修饰。前哨特异的蛋白酶1(SENP1)参与了SUMO蛋白的成熟过程，另一方面，SENP1还参与了SUMO的解离，使靶蛋白从SUMO中解离出来，防止靶蛋白的进一步降解。在本研究中，我们建立了对伊立替康(CPT-11)耐药的人结肠癌LoVo株(LoVo(R-CPT-11))，以探讨SENP1在结直肠癌耐药中的作用。在LoVo(R-CPT-11)细胞中，SENP1和HIF-1α蛋白大量积聚，相扑途径酶增加，而增殖、血管生成和糖酵解等蛋白标志物表达上调。SENP1基因的敲除降低了LoVo(R-CPT-11)细胞的迁移能力，并触发了对CPT-11处理的重新敏感性。利用GEPIA网络服务器对TCGA/GTEx数据库中SENP1和HIF-1α基因表达的分析表明，在结直肠癌患者中SENP1和HIF-1α的表达呈正相关，这两个基因的高表达可能预示着不良的临床预后。结论：SENP1可能在结直肠癌对CPT-11耐药中起重要作用。靶向SENP1以降低耐药特性可在前瞻性临床研究中考虑。
Colorectal cancer is one of the most prevalent cancers in the world. Chemoresistance has always been a problem encountered in its treatment. It is known that SUMOylation may regulate protein stability and decomposition, and even affect the protein translocation and posttranslational modification in cells. Sentrin-specific protease 1 (SENP1) is involved in the maturation of SUMO protein, and on the other hand, plays a role in deSUMOylation, which dissociates the target protein from SUMO and prevents further degradation of the target protein. In this study, we established an Irinotecan (CPT-11) resistant human colon cancer LoVo strain (LoVo(R-CPT-11)) to investigate the role of SENP1 in the development of drug resistance in colorectal cancer. The abundant accumulation of SENP1 and HIF-1 alpha proteins and the increase of SUMO pathway enzymes were observed in LoVo(R-CPT-11) cells while the protein markers of proliferation, angiogenesis, and glycolysis were upregulated. Knockdown of SENP1 reduced the migration ability and trigged re-sensitivity of LoVo(R-CPT-11) cells to CPT-11 treatment. The analysis of SENP1 and HIF-1 alpha gene expressions from TCGA/GTEx datasets using the GEPIA web server showed a positive correlation between SENP1 and HIF-1 alpha in colorectal cancer patients and the high expression of these two genes might predict a poor outcome clinically. In conclusion, SENP1 might play an important role in CPT-11 resistance in colorectal cancer. Targeting SENP1 to reduce the resistant property could be considered in prospective clinical studies.