Destablilization of TRAF6 by DRAK1 Suppresses Tumor Growth and Metastasis in Cervical Cancer Cells.
The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) inhibits the proinflammatory signaling pathway by targeting TRAF6 for degradation, thereby ... suppressing inflammatory signaling-mediated tumor growth and metastasis in advanced cervical cancer cells. DRAK1 bound directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering with homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1? signaling-associated pathway and proinflammatory cytokine production. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel antagonist of inflammation targeting TRAF6 for degradation that limits inflammatory signaling-mediated progression of advanced cervical cancer. SIGNIFICANCE: Serine/threonine kinase DRAK1 serves a unique role as a novel negative regulator of the inflammatory signaling mediator TRAF6 in cervical cancer progression.
Mesh Terms:
Animals, Apoptosis Regulatory Proteins, Autophagy, Cell Line, Tumor, Disease Progression, Down-Regulation, Female, Gene Expression Regulation, Neoplastic, Humans, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, Mice, Neoplasm Staging, Protein Binding, Protein Domains, Protein Multimerization, Protein Stability, Protein-Serine-Threonine Kinases, Proteolysis, Signal Transduction, Tissue Array Analysis, Ubiquitination, Uterine Cervical Neoplasms, Xenograft Model Antitumor Assays
Animals, Apoptosis Regulatory Proteins, Autophagy, Cell Line, Tumor, Disease Progression, Down-Regulation, Female, Gene Expression Regulation, Neoplastic, Humans, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, Mice, Neoplasm Staging, Protein Binding, Protein Domains, Protein Multimerization, Protein Stability, Protein-Serine-Threonine Kinases, Proteolysis, Signal Transduction, Tissue Array Analysis, Ubiquitination, Uterine Cervical Neoplasms, Xenograft Model Antitumor Assays
Cancer Res
Date: Dec. 15, 2019
PubMed ID: 32265222
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