The NEDD8-activating enzyme inhibition with MLN4924 sensitizes human cancer cells of different origins to apoptosis and necroptosis

• Published in: Archives of biochemistry and biophysics 2020-09, Vol.691, p.108513, Article 108513
• Main Authors: El-Mesery, Mohamed, Anany, Mohamed A., Hazem, Sara H., Shaker, Mohamed E.
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Cell Line, Tumor; Cyclopentanes - pharmacology; Enzyme Inhibitors - pharmacology; Humans; MLN4924; Necroptosis; Necroptosis - drug effects; NEDD8-Activating enzyme; NF-kappa B - metabolism; NF-κB; Pyrimidines - pharmacology; Signal Transduction - drug effects; TNF; Tumor Necrosis Factor-alpha - pharmacology; Ubiquitin-Activating Enzymes - antagonists & inhibitors
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2020.108513

MLN4924 is an inhibitor of NEDD8-activating enzyme (NAE) that interferes with the cullin-RING ubiquitin ligase complexes formation and the nuclear factor kappa B (NF-κB) activation. Here, we investigated the cytotoxic effect of MLN4924 and its ability to sensitize a broad range of cancer cells of different origins to tumour necrosis factor-α (TNF)-induced cell death alongside unravelling its mechanism of action. Cell viability and caspases processing were determined after MLN4924 treatment either alone or with zVAD-fmk (pan caspase inhibitor), necrostatin-1 (nec-1, RIPK1 inhibitor) and necrosulfonamide (NSA, MLKL inhibitor). Moreover, MLN4924 ability to potentiate TNF-induced cell death was evaluated in 24 cell lines of different cancer origins. The impact of NAE inhibition with MLN4924 on TNF-induced apoptosis and necroptosis was evaluated using zVAD-fmk and nec-1, respectively. MLN4924 alone was able to induce cell death in different cell lines that was attributed to apoptosis induction. Also, MLN4924 sensitized different cancer cell lines to TNF-induced cell death. MLN4924/TNF-induced cell death was apoptosis and necroptosis dependent that may be attributed to MLN4924 inhibition of NF-κB pathway activation. Targeting NAE and NF-κB pathway with MLN4924 represents a substantial approach to enhance the sensitivity of diverse types of cancer cells. Moreover, the broad in vitro screening of MLN4924 anticancer activity provides a valuable guidance for elucidating the susceptible cancer types for the prospective clinical application of MLN4924. •Targeting NAE with MLN4924 induces apoptosis in cancer cells of different origins.•MLN4924 sensitizing effect to cancer cells is apoptosis and necroptosis dependent.•Targeting NAE and NF-κB pathway with MLN4924 represents a substantial approach to enhance the sensitivity of cancer cells•The current in vitro study specifies the susceptible cancer types for the prospective clinical applications of MLN4924.