Abstract
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 IL1β 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.
Highlights
Cervical cancer is a major cause of mortality in women worldwide and strongly associated with persistent infection with high-risk (HR) human papillomavirus (HPV), mainly HPV16 and HPV18 [1, 2]
We show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) decreases the stability of the TNF receptor-associated factor 6 (TRAF6) protein via an autophagy-mediated degradation pathway by interfering with the homo-oligomerization of TRAF6, eventually suppressing tumor growth and metastasis in inflammationassociated advanced cervical cancer cells
Considering that the TRAF domain of TRAF6 is important for the autoubiquitination of TRAF6 through homooligomerization-mediated its stabilization, we examined whether DRAK1 inhibits the autoubiquitination of TRAF6
Summary
Cervical cancer is a major cause of mortality in women worldwide and strongly associated with persistent infection with high-risk (HR) human papillomavirus (HPV), mainly HPV16 and HPV18 [1, 2]. Most HPV viruses can be cleared by the immune system, and a preventive and effective vaccine against HPV infection decreases the development of cervical cancer [3,4,5]. Approximately 1% of HPV-positive patients infected with HR-HPV eventually develop advanced cervical cancer from premalignant lesions [6], indicating that not all HPV infections progress into cervical cancer. Pang contributed as the co-senior authors of this article
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
