Qiu Guo-Hua, Que Wutang, Yan Shanying, Zheng Xintian, Xie Xiaojin, Huang Cuiqin, Yang Xiaoyan, Hooi Shing Chuan
Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan University, Longyan, 364012, Fujian, People's Republic of China.
Key Laboratory of Preventive Veterinary Medicine and Biotechnology, Fujian Province Universities, Longyan University, Longyan, 364012, Fujian, People's Republic of China.
Cytotechnology. 2019 Feb;71(1):23-33. doi: 10.1007/s10616-018-0258-9. Epub 2019 Jan 3.
The tumor suppressor DLEC1 has been shown to promote cell proliferation when AP-2α2 is down-regulated in HCT116 stable clones, suggesting its pro-survival nature. However, the pro-survival function of DLEC1 has not been confirmed in other cells and its underlying mechanisms remain elusive. Therefore, we knocked down DLEC1 in a panel of cell lines and found that DLEC1 depletion caused various extents of cell death through intrinsic pathway. DLEC1 overexpression promoted cell survival and reduced cell death in cancer cells after 5-FU treatment, while DLEC1 down-regulation sensitized cancer cells to 5-FU. Further studies demonstrated that DLEC1 attenuated the increase in cleaved PARP, caspase-3 and caspase-7, the activity of caspase-9 and the diffusion of cytosolic cytochrome c from mitochondria. Our data also showed that BCL-XL was up-regulated by DLEC1 in stable clones after 5-FU treatment. Altogether, these results indicated that DLEC1 protects cells against cell death induced by 5-FU through the attenuation of active proteins in caspase cascade and the up-regulation of BCL-XL. Therefore, DLEC1 can be a pro-survival protein under certain circumstances and a potential therapeutic target for increasing sensitivity of cancer cells to 5-FU.
肿瘤抑制因子DLEC1已被证明，在HCT116稳定克隆中，当AP - 2α2下调时可促进细胞增殖，这表明其具有促生存的特性。然而，DLEC1的促生存功能尚未在其他细胞中得到证实，其潜在机制仍不清楚。因此，我们在一组细胞系中敲低DLEC1，发现敲低DLEC1会通过内源性途径导致不同程度的细胞死亡。DLEC1过表达促进了5 - FU处理后癌细胞的存活并减少了细胞死亡，而DLEC1下调则使癌细胞对5 - FU敏感。进一步研究表明，DLEC1减弱了裂解的PARP、caspase - 3和caspase - 7的增加、caspase - 9的活性以及细胞溶质细胞色素c从线粒体的扩散。我们的数据还显示，在5 - FU处理后的稳定克隆中，DLEC1上调了BCL - XL。总之，这些结果表明，DLEC1通过减弱caspase级联反应中的活性蛋白和上调BCL - XL来保护细胞免受5 - FU诱导的细胞死亡。因此，DLEC1在某些情况下可能是一种促生存蛋白，并且是提高癌细胞对5 - FU敏感性的潜在治疗靶点。
