In this study, we show that downregulation of DRAK1 expression is associated with paclitaxel resistance in cervical cancer cells and that DRAK1 protein is degraded by CUL3/SPOP E3 ubiquitin ligase through K48-linked polyubiquitination-mediated proteasomal degradation in paclitaxel-resistant cells, resulting in an increase in TRAF6 levels and TRAF6-mediated NF-κB activation, thereby promoting tumor progression. This evidence concerns the gene CUL3 and cervical cancer.