Abstract
Chemotherapy and ionizing radiation (IR) can induce autophagy in tumor cells. Here, we report that the level of autophagy in tumor cells was related to the background of p53 gene that NF-κB acts as a negative regulator of autophagy in mutant p53 (p53-R273H) cells, and that acetylation was involved in the IR-induced nuclear translocation of NF-κB. We found that autophagy-related proteins were highly expressed in wild-type p53 (wt-p53) cells and that IR increased their levels further. p53-R273H cells exhibited low levels of autophagy; there was no change following IR treatment. The nuclear translocation of p65 was upregulated in p53-R273H cells following IR; when p65 was competitively inhibited from entering the nucleus with SN50, the level of autophagy increased. The nuclear translocation of p65 was mediated by p300; this factor also regulates the nuclear behavior of NF-κB. The knockdown of p300 in p53-R273H cells led to an inhibition of p65 expression and an increase in autophagy. In addition, the inhibition of p300 or p65 not only activated autophagy, it also induced radiosensitivity in p53-R273H cells. The relationship between the p53 gene, NF-κB, and autophagy was further analyzed in a mouse model of xenograft tumors and in clinical tumor pathological specimens; the results were consistent with the in vitro experiments. Our findings indicate that autophagy may be regulated by NF-κB in p53-R273H cells. These findings may help to improve the therapeutic strategy adopted for tumors related to the mutant p53-R273H gene; such therapy would aim to target NF-κB to induce autophagy.
Highlights
Autophagy is a process in which cells use lysosomes to degrade their damaged organelles and macromolecules
When RNAi is used to interfere with NF-κB, the gain-of- function (GOF) These results showed that the inhibitory effect of ionizing radiation (IR) on wild-type phenomenon in cancer cell lines is reduced, suggesting the p53 cells was more obvious than that on mutant p53-R273H cells
In this study, we found that the expression levels of the p53 gene can influence the basic levels of autophagy in cells, and that mutation in the p53 gene mediates the regulation of autophagy cells
Summary
Autophagy is a process in which cells use lysosomes to degrade their damaged organelles and macromolecules. This represents an important regulatory mechanism for cell growth, differentiation, maturation, and death, but is related to a variety of human diseases, including tumors [1]. Previous studies in our laboratory have shown that activation of autophagy increases the sensitivity of glioma stem cells to IR [5]. It is still unclear whether autophagy should be induced or suppressed when treating tumors
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