Neddylation Activating Enzyme Inhibitor PEV Enhances the Sensitivity of Colorectal Cancer Cells to 5-Fluorouracil through Cell Senescence
Cell senescence is closely related to the slowing down of tumor cell proliferation,and cell se-nescence 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 im-prove 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.Throughβ-galactosidase staining,Western blot,cell count for three days,CCK-8 test,mice and xenograft models,immuno-histochemistry 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 ef-fect on cell proliferation was more significant.The results showed that compared with the solvent group,the galac-tosidase 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 in-hibited cell proliferation more significantly.This study revealed that NEDD8-activating enzyme inhibitor PEV pro-motes cell senescence and increases the sensitivity of colorectal cancer to 5-FU,which aggravates cell senescence and inhibits cell proliferation.
neddylationcellular senescencecolorectal cancerchemotherapy drug sensitivity
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