Degradation of DRAK1 by CUL3/SPOP E3 Ubiquitin ligase promotes tumor growth of paclitaxel-resistant cervical cancer cells.
Kyoungwha PangJihee LeeJunil KimJinah ParkYuna ParkEunji HongHaein AnAkira OoshimaMinjung SonKyung Soon ParkJae-Hyun ChoCheol LeeYong-Sang SongKyung-Min YangSeong-Jin KimPublished in: Cell death & disease (2022)
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.
Keyphrases
- nuclear factor
- protein protein
- poor prognosis
- chemotherapy induced
- binding protein
- protein kinase
- toll like receptor
- small molecule
- cell cycle arrest
- oxidative stress
- rheumatoid arthritis
- signaling pathway
- induced apoptosis
- tyrosine kinase
- squamous cell carcinoma
- case report
- emergency department
- inflammatory response
- endoplasmic reticulum stress
- pi k akt
- risk assessment
- human health
- electronic health record
- tissue engineering