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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Skp2 is associated with paclitaxel resistance in prostate cancer cells
Yeguo Yang1, Yi Lu1, Lihui Wang1
1Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education, Nanning, Guangxi 530021, P.R. China.
Abstract:
Prostate cancer is the most commonly diagnosed tumor in men in the United States. Patients with hormone-refractory prostate cancer are often treated with paclitaxel, but most of them eventually develop drug resistance. S-phase kinase associated protein 2 (Skp2) is a component of the SCF (Skp1-Cullin1-F-box) type of E3 ubiquitin ligase complexes. In the present study, we investigated the role of Skp2 in paclitaxel-resistant DU145-TxR or PC-3-TxR cells by Skp2 silencing or using Skp2 inhibitors. We first confirmed that Skp2 expression is up-regulated in DU145-TxR or PC-3-TxR cells compared with their parental cells DU145 or PC-3, respectively. Knockdown of Skp2 or Skp2 inhibitor treatment in DU145-TxR or PC-3-TxR cells restored paclitaxel sensitivity. E-cadherin was decreased while Vimentin was increased in PC-3-TxR or DU145-TxR cells. In addition, p27 expression was inversely correlated with Skp2 expression in DU145-TxR or PC-3-TxR cells. Moreover, p27 was found to increase in both Skp2 silencing PC-3-TxR and DU145-TxR cells. These results suggest that Skp2 is associated with prostate cancer cell resistance to paclitaxel. Skp2 may be a potential therapeutic target for drug-resistant prostate cancer.
Insights
S-phase kinase associated protein 2 (Skp2) is upregulated in drug-resistant prostate cancer cells. Silencing Skp2 or using inhibitors restored sensitivity to paclitaxel, suggesting Skp2 as a therapeutic target for resistant prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer is a common malignancy in the US.
- Hormone-refractory prostate cancer patients often receive paclitaxel treatment.
- Paclitaxel resistance is a significant clinical challenge in treating advanced prostate cancer.
Purpose of the Study:
- To investigate the role of S-phase kinase associated protein 2 (Skp2) in paclitaxel resistance in prostate cancer cells.
- To determine if targeting Skp2 can overcome paclitaxel resistance.
Main Methods:
- Utilized Skp2 silencing (knockdown) and Skp2 inhibitors in paclitaxel-resistant prostate cancer cell lines (DU145-TxR and PC-3-TxR).
- Assessed changes in paclitaxel sensitivity, Skp2 expression, E-cadherin, Vimentin, and p27 expression.
- Compared Skp2 expression in resistant cells versus parental cells.
Main Results:
- Skp2 expression was significantly higher in paclitaxel-resistant prostate cancer cells (DU145-TxR, PC-3-TxR) compared to their parental counterparts.
- Skp2 knockdown or inhibition restored sensitivity to paclitaxel in resistant cells.
- Skp2 inhibition affected epithelial-mesenchymal transition markers (decreased E-cadherin, increased Vimentin) and increased p27 expression, which was inversely correlated with Skp2 levels.
Conclusions:
- Skp2 plays a crucial role in the development of paclitaxel resistance in prostate cancer.
- Targeting Skp2 presents a promising therapeutic strategy for overcoming drug resistance in prostate cancer.
- Modulating Skp2 may impact cellular pathways involved in drug resistance and metastasis.
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