MLN4924 suppresses kidney renal clear cell carcinoma progression through coordinated inhibition of Cullin1 neddylation and PSMB10-associated NF-κB inflammatory signaling.

BACKGROUND

Kidney renal clear cell carcinoma (KIRC) is characterized by malignant progression, inflammatory signaling, and therapeutic resistance. This study investigated whether MLN4924, a selective NEDD8-activating enzyme inhibitor, suppresses KIRC progression through coordinated regulation of Cullin1 neddylation, PSMB10 expression, and NF-κB signaling.

METHODS

KIRC cells were treated with MLN4924, followed by Western blotting, transcriptomic sequencing, pathway enrichment analysis, PSMB10 knockdown, and NF-κB pathway assessment. Complementary PSMB10 overexpression rescue experiments, together with colony formation and Transwell assays, were performed to test whether restoration of PSMB10 could reverse MLN4924-induced NF-κB inhibition and associated malignant phenotypes. A 786-O nude mouse xenograft model was used to evaluate the in vivo antitumor effects, tolerability, histological alterations, and molecular mechanisms of MLN4924.

RESULTS

MLN4924 inhibited renal cancer cell growth and markedly reduced Cullin1-NEDD8 and PSMB10 protein levels. Transcriptomic analysis revealed extensive remodeling of lipid and sterol metabolism, extracellular matrix organization, cytokine and inflammatory signaling, growth factor-related pathways, and DNA replication-associated processes. MLN4924 treatment and PSMB10 knockdown both suppressed p65 phosphorylation, while combined intervention further inhibited phosphorylation of p65, IKKα/β, and IκBα. Conversely, PSMB10 overexpression partially restored p65 phosphorylation in MLN4924-treated ACHN and 786-O cells and significantly recovered colony formation, migration, and invasion. In vivo, MLN4924 significantly reduced tumor volume and weight, with an inhibition rate exceeding 30% and acceptable tolerability. Treated tumors showed increased apoptosis and necrosis, decreased Cullin-NEDD8, PSMB10, phospho-p65, TNF-α, IL-6, EMT/ECM remodeling markers, and proliferation-related proteins, and enhanced apoptotic signaling.

CONCLUSION

MLN4924 suppresses KIRC progression through inhibition of neddylation and attenuation of PSMB10-associated IKK/IκB/p65 NF-κB inflammatory signaling.