Abstract
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 IC50 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.
Highlights
Taxane-based chemotherapy is chosen as a single agent or combination with cisplatin to treat patients with recurrent or advanced cervical cancer; cancer resistance is an emerging problem that remains to be solved [1, 2]
As Tumor necrosis factor receptor-associated factor 6 (TRAF6) cancer cells and that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) protein is degraded by Cullin scaffold protein 3 (CUL3)/SPOP E3 levels were induced in HeLa/PTX cells, we investigated ubiquitin ligase through K48-linked polyubiquitination-mediated whether knockdown of TRAF6 resulted in attenuation of the cell proteasomal degradation in paclitaxel-resistant cells, resulting in proliferation rate of HeLa/PTX cells
We examined the expressions of genes ABCB1, IL-1β, and IL-8 in HeLa/ PTX cells, the NF-κB target genes, which were enhanced in DRAK1
Summary
Taxane-based chemotherapy is chosen as a single agent or combination with cisplatin to treat patients with recurrent or advanced cervical cancer; cancer resistance is an emerging problem that remains to be solved [1, 2]. Much progress has been made in understanding the mechanisms of cellular resistance, including the expression of multidrug resistance proteins, reduced drug accumulation, enhanced DNA repair, aberrant apoptosis pathways, and altered cell proliferation, there has been no significant biomarkers discovered to predict the recurrence of cervical cancer [3,4,5]. The nuclear factor-kappa B (NF-κB) signaling pathway is activated by chemotherapy drugs, such as platinum-based anticancer drugs, anthracyclines, and taxanes, and its induction impinges on cellular resistance to anticancer agents [6,7,8]. The function of TRAF6 in inflammation and cancer progression has been widely studied, its role in paclitaxel sensitivity remains to be examined
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