Neddylation Activating Enzyme Inhibitor PEV Enhances the Sensitivity of Colorectal Cancer Cells to 5-Fluorouracil through Cell Senescence
HUA Yuxin1,2, NI Mengzhen2, SUN Qingqing2, ZHAI Xiaoqing2, PAN Weiwei2 *
Cell senescence is closely related to the slowing down of tumor cell proliferation, and cell senescence inhibits the activation of many oncogenes. Therefore, inducing cell senescence is a potential strategy to interfere with the important process of tumor cells proliferation at this stage, and may be an effective way to treat tumors. PEV (Pevonedistat), also known as MLN4924, is a NAE (NEDD8-activating enzyme) inhibitor that can inactivate CRL by blocking Cullin neddylation. PEV can inhibit the proliferation of tumor cells, promote cell apoptosis and senescence. 5-FU (5-fluorouracil) is a first-line chemotherapy agent in the treatment of colorectal cancer. However, it is not known whether PEV can enhance the sensitivity of chemotherapy drug 5-FU and improve the therapeutic effect of colorectal cancer by promoting cell senescence. In this study, colorectal cancer cells HCT116 and HT29 were treated with PEV alone, 5-FU alone and PEV combined with 5-FU respectively. Through β-galactosidase staining, Western blot, cell count for three days, CCK-8 test, mice and xenograft models, immunohistochemistry and other experiments, it was proved that PEV promoted cell senescence, the combination of PEV and 5-FU accelerated cell senescence and increased the sensitivity of colorectal cancer to 5-FU. The inhibitory effect on cell proliferation was more significant. The results showed that compared with the solvent group, the galactosidase activity, the expression of senescence-related proteins such as P21, P27, PAI-1, P62 and the loss of nuclear morphological marker LaminB1 were increased in PEV plus PEV and 5-FU groups. At the same time, compared with PEV single drug treatment group, PEV and 5-FU combined treatment group increased cell senescence and inhibited cell proliferation more significantly. This study revealed that NEDD8-activating enzyme inhibitor PEV promotes cell senescence and increases the sensitivity of colorectal cancer to 5-FU, which aggravates cell senescence and inhibits cell proliferation.
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