Zhang Xueyan, Dong Yalong, Li Wenbo, He Mingjing, Shi Yangyang, Han Shuhua, Li Linlin, Zhao Jinzhu, Li Leilei, Huo Junfeng, Liu Xiaojie, Ji Yanting, Liu Qi, Wang Cong
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China.
Life Sci. 2024 Apr 15;343:122530. doi: 10.1016/j.lfs.2024.122530. Epub 2024 Feb 23.
Cancer cell resistance presents a significant clinical challenge. The mechanisms underlying drug resistance in cancer cells are intricate and remain incompletely understood. Notably, tumor cell resistance often coincides with the epithelial-mesenchymal transition (EMT). In this study, we observed an elevation in autophagy levels following the development of drug resistance in oesophageal cancer cells. Inhibition of autophagy led to a reduction in drug-resistant cell migration and the inhibition of EMT. Furthermore, we identified an upregulation of SIRT1 expression in drug-resistant oesophageal cancer cells. Subsequent inhibition of SIRT1 expression in drug-resistant cells resulted in the suppression of autophagy levels, migration ability, and the EMT process. Our additional investigations revealed that a SIRT1 inhibitor effectively curbed tumor growth in human oesophageal cancer xenograft model mice (TE-1, TE-1/PTX) without evident toxic effects. This mechanism appears to be associated with the autophagy levels within the tumor tissue.
癌细胞耐药性是一个重大的临床挑战。癌细胞耐药的潜在机制错综复杂，目前仍未完全明确。值得注意的是，肿瘤细胞耐药性常与上皮-间质转化（EMT）同时出现。在本研究中，我们观察到食管癌细胞产生耐药性后自噬水平升高。抑制自噬导致耐药细胞迁移减少以及EMT受到抑制。此外，我们发现耐药食管癌细胞中SIRT1表达上调。随后抑制耐药细胞中SIRT1的表达导致自噬水平、迁移能力及EMT过程受到抑制。我们的进一步研究表明，一种SIRT1抑制剂可有效抑制人食管癌异种移植模型小鼠（TE-1、TE-1/PTX）的肿瘤生长，且无明显毒性作用。该机制似乎与肿瘤组织内的自噬水平有关。
