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Updated: Jul 6, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Pretreatment of docetaxel enhances TRAIL-mediated apoptosis in prostate cancer cells
Jinsang Yoo1, Sung-Soo Park, Yong J Lee
1Department of Surgery and Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent because of its tumor selectivity. TRAIL is known to induce apoptosis in cancer cells but spare most normal cells. In this study, we examined whether treatment of docetaxel (DTX) can enhance apoptotic cell death by TRAIL against androgen-independent prostate cancer (AIPC). The cell death effect of combinations of TRAIL and docetaxel on prostate cancer cell lines (androgen-dependent LNCaP and its derived androgen-independent, metastatic C4-2B) was evaluated by synergisms of apoptosis. Western blot assay and DNA fragmentation assay were used to study the underlying mechanisms of cell death and search for any mechanisms of enhancement of TRAIL induced apoptosis in the presence of docetaxel. In addition, we investigated the in vitro anti-tumor effects of combined docetaxel and TRAIL using MAP kinase inhibitors. Docetaxel itself could not induce apoptotic cell death in 24 h even in high concentration. Apoptotic cell death, however, was drastically enhanced by pretreatment of docetaxel 20 h before TRAIL treatment. Docetaxel enhanced the PARP-1 cleavage and caspases activation by TRAIL especially in androgen-independent, metastatic C4-2B cell line, mainly by phosphorylation of Bcl-2 by JNK activation. It appears that apoptotic cell death was protected by the JNK inhibitor SP600125. The results of our study show that pretreatment of docetaxel is able to enhance the apoptosis produced by TRAIL in prostate cancer cells, especially in hormone-refractory prostate cancer (HRPC).
Insights
Pretreating prostate cancer cells with docetaxel significantly enhances apoptosis induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL). This combination therapy shows promise for hormone-refractory prostate cancer, overcoming resistance to TRAIL alone.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits tumor selectivity, inducing apoptosis in cancer cells while sparing normal cells.
- Androgen-independent prostate cancer (AIPC) presents a therapeutic challenge due to resistance to conventional treatments.
- Docetaxel (DTX) is a chemotherapy agent, but its ability to induce apoptosis alone is limited.
Purpose of the Study:
- To investigate the potential of docetaxel (DTX) to enhance TRAIL-induced apoptosis in androgen-independent prostate cancer (AIPC).
- To elucidate the molecular mechanisms underlying the synergistic effects of combined DTX and TRAIL treatment.
Main Methods:
- Evaluation of cell death and synergistic apoptosis in prostate cancer cell lines (LNCaP and C4-2B) using combinations of DTX and TRAIL.
- Western blot assays and DNA fragmentation assays to analyze cell death mechanisms.
- Investigation of in vitro anti-tumor effects using MAP kinase inhibitors, including JNK inhibitors.
Main Results:
- Docetaxel alone did not induce significant apoptosis within 24 hours, even at high concentrations.
- Pretreatment with docetaxel for 20 hours dramatically enhanced TRAIL-induced apoptotic cell death, particularly in the metastatic C4-2B cell line.
- Docetaxel enhanced TRAIL-induced Poly (ADP-ribose) polymerase 1 (PARP-1) cleavage and caspase activation, primarily through JNK-mediated phosphorylation of Bcl-2.
- Inhibition of JNK signaling with SP600125 protected cells from apoptosis, indicating JNK's crucial role.
Conclusions:
- Pretreatment with docetaxel is an effective strategy to enhance TRAIL-induced apoptosis in prostate cancer cells.
- This combination therapy is particularly promising for hormone-refractory prostate cancer (HRPC), suggesting a potential new therapeutic approach.
- The enhancement of TRAIL-induced apoptosis by docetaxel involves JNK activation and subsequent Bcl-2 phosphorylation.
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