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Neddylation inhibition activates the protective autophagy through NF-?B-catalase-ATF3 Axis in human esophageal cancer cells.

ABSTRACT: BACKGROUND:Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition could induce autophagy in esophageal cancer cells and affect the expression of other members of ATF/CREB subfamily, such as ATF3. METHODS:The expression of relevant proteins of NF-?B/Catalase/ATF3 pathway after neddylation inhibition was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. ROS generation upon MLN4924 treatment was determined by H2-DCFDA staining. The proliferation inhibition induced by MLN4924 was evaluated by ATPLite assay and apoptosis was evaluated by Annexin V /PI double staining. RESULTS:For the first time, we reported that MLN4924, a specific inhibitor of Nedd8-activating enzyme, promoted the expression of ATF3 to induce autophagy in esophageal cancer. Mechanistically, MLN4924 inhibited the activity of CRLs and induced the accumulation of its substrate I?B? to block NF-?B activation and Catalase expression. As a result, MLN4924 activated ATF3-induced protective autophagy, thereby inhibiting MLN4924-induced apoptosis, which could be alleviated by ATF3 silencing. CONCLUSIONS:In our study, we elucidates a novel mechanism of NF-?B/Catalase/ATF3 pathway in MLN4924-induced protective autophagy in esophageal cancer cells, which provides a sound rationale and molecular basis for combinational anti-ESCC therapy with knockdown ATF3 and neddylation inhibitor (e.g. MLN4924). Video abstract.

SUBMITTER: Liang Y

PROVIDER: S-EPMC7218644 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells.

Liang Yupei Y Jiang Yanyu Y Jin Xing X Chen Ping P Heng Yongqing Y Cai Lili L Zhang Wenjuan W Li Lihui L Jia Lijun L

Cell communication and signaling : CCS 20200512 1

<h4>Background</h4>Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition could induce autophagy in esophageal cancer cells and affect the expression of other members of ATF/CREB subfamily, such as ATF3.<h4>Methods</h4>The expression of relevant proteins of NF-κB/Catalase/ATF3 ...[more]

PMID: 32398095

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Project description:Upregulation of protein neddylation occurs in numerous types of human cancer, including liver cancer. MLN4924, a potent neddylation‑inhibiting pharmacological agent, demonstrates anticancer ability in numerous cancers. However, the sensitivity of MLN4924 in liver cancer remains unsatisfactory due to factors causing resistance. RT‑qPCR and western blotting were utilized to assess the mRNA and protein levels of genes, respectively. Cell Counting Kit‑8 assay and colony formation assays were employed to assess cell viability and proliferation. The pathway of protein degradation and stability were determined by western blotting after treatment with MG132 and cycloheximide. An immunoprecipitation assay was utilized to detect the ubiquitination of protein. An in vitro ubiquitination assay was used to determine the ubiquitin linkage. To the best of our knowledge, the present study was the first to demonstrate that NF‑κB inhibitor α (IκBα) downregulation and subsequent inflammation in response to MLN4924 limited the antitumor potential of MLN4924. Ectopic expression of IκBα enhanced the antitumor potential of MLN4924 in liver cancer cells. Moreover, the results of the present study demonstrated that MLN4924 decreased IκBα via promoting the K48 linkage of ubiquitin to IκBα. Mechanistic studies demonstrated that MLN4924 enhanced the protein stability of β‑transducin repeat‑containing protein (β‑TrCP), promoting the ubiquitination of IκBα, which led to the ubiquitin‑mediated degradation of IκBα. In addition, the results of the present study also demonstrated that β‑TrCP knockdown markedly inhibited MLN4924 from suppressing the growth of liver cancer cells, via attenuating MLN4924‑mediated IκBα downregulation and inflammation. Collectively, these results indicated that the β‑TrCP/IκBα/inflammation pathway may act as a novel resistance factor of MLN4924, and targeting β‑TrCP may be beneficial for the treatment of liver cancer.

Dataset Information

Neddylation inhibition activates the protective autophagy through NF-?B-catalase-ATF3 Axis in human esophageal cancer cells.

Publications

Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells.

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