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Degradation of DRAK1 by CUL3/SPOP E3 Ubiquitin ligase promotes tumor growth of paclitaxel-resistant cervical cancer cells
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Degradation of DRAK1 by CUL3/SPOP E3 Ubiquitin ligase promotes tumor growth of paclitaxel-resistant cervical cancer cells
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Journal Article
Degradation of DRAK1 by CUL3/SPOP E3 Ubiquitin ligase promotes tumor growth of paclitaxel-resistant cervical cancer cells
2022
Overview
Despite favorable responses to initial chemotherapy, drug resistance is a major cause limiting chemotherapeutic efficacy in many advanced cancers. However, mechanisms that drive drug-specific resistance in chemotherapy for patients with advanced cancers are still unclear. Here, we report a unique role of death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) associated with paclitaxel resistance in cervical cancer cells. Interestingly, DRAK1 protein level was markedly decreased in paclitaxel-resistant cervical cancer cells without affecting its mRNA expression, which resulted in an increase in tumor necrosis factor receptor-associated factor 6 (TRAF6) expression, as well as an activation of TRAF6-mediated nuclear factor-kappa B (NF-κB) signaling cascade, thereby promoting tumor progression. DRAK1 depletion markedly increased the chemotherapeutic IC
50
values of paclitaxel in cervical cancer cells. Ectopic expression of DRAK1 inhibited growth of paclitaxel-resistant cervical cancer cells in vitro and in vivo. Furthermore, DRAK1 was markedly underexpressed in chemoresistant cervical cancer patient tissues compared with chemosensitive samples. We found that DRAK1 protein was destabilized through K48-linked polyubiquitination promoted by the Cullin scaffold protein 3 (CUL3) / speckle-type POZ (poxvirus and zinc finger protein) protein (SPOP) E3 ubiquitin ligase in paclitaxel-resistant cells. Collectively, these findings suggest that DRAK1 may serve as a potential predictive biomarker for overcoming paclitaxel resistance in cervical cancer.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/105
/ 13/31
/ 13/89
/ 14/63
/ 38/77
/ 38/91
/ 64/60
/ 82/51
/ Apoptosis Regulatory Proteins - genetics
/ Apoptosis Regulatory Proteins - metabolism
/ Biomedical and Life Sciences
/ Cervix
/ Cullin
/ Cullin Proteins - metabolism
/ Death-associated protein kinase
/ Female
/ Humans
/ Kinases
/ Nuclear Proteins - metabolism
/ Paclitaxel - therapeutic use
/ Protein Serine-Threonine Kinases - genetics
/ Protein Serine-Threonine Kinases - metabolism
/ Proteins
/ Repressor Proteins - genetics
/ Repressor Proteins - metabolism
/ TNF Receptor-Associated Factor 6 - metabolism
/ Ubiquitin-Protein Ligases - genetics
/ Ubiquitin-Protein Ligases - metabolism
/ Uterine Cervical Neoplasms - drug therapy
