The Effect And Mechanism Of IASPP-Nrf2 In Regulating Cancer Cellular Senescence In Cytoplasm

Cellular senescence is a permanent cell cycle arrest,often accompanied by the production of multiple senescence-associated secretory phenotypes.In addition to promoting cell apoptosis,inducing cellular senescence is also a significant mechanism for radiotherapy and chemotherapy and certain molecular targeted drugs to inhibit tumors.However,cellular senescence,as a self-protective mechanism of cells,has advantages and disadvantages in tumor treatment.According to our previous research results reported on tumor cellular senescence,iASPP significantly inhibits the occurrence of cellular senescence in the nucleus.However,the functional mechanism of iASPP increased in the cytoplasm of cancer cells under senescence has not yet been elucidated.First,the common clinical chemotherapy drug Doxorubicin was selected to induce cellular senescence in colorectal cancer cell line HCT116 and breast cancer cell line MCF-7,and successfully established a cancer cellular senescence model.Compared with the control group without cellular senescence,the positive rate ofβ-Gal staining of senescent cancer cells is significantly positively correlated with the degree of celullar senescence.Compared with the control group,the protein levels of iASPP and Nrf2 molecules in senescent cancer cells show an upward trend,and the molecular marker of cellular senescence,LMNB1,shows a downward trend.Notably,by the co-immunoprecipitation experiments,iASPP in the cancer cytoplasm can still competitively bind to Keap1 of the main inhibitor of Nrf2 with Nrf2 under the condition of cellular senescence,and the increased iASPP in the cytoplasm can stabilize Nrf2 without being degraded.Our experiments have found that changes in iASPP-Nrf2 in cancer cells under senescence can cause changes in the secretion of macrophage colony-stimulating factor(M-CSF)and other senescence-associated secretory phenotypes(SASP).Further studies have shown that Nrf2 as a transcription factor can activate the transcription and expression of M-CSF,thereby regulating the tumor immune microenvironment.In conclusion,consistent with previous research results,the senescence of cancer cells induced by chemotherapy drugs will increase the protein expression level of iASPP in the cytoplasm,and inhibit the degradation of Nrf2 protein,cause Nrf2 to enter the nucleus to regulate the transcription and expression of M-CSF and secrete into the tumor microenvironment to further regulate the biological functions of other components in the microenvironment.