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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Protein Disulfide Isomerase 4 Drives Docetaxel Resistance in Prostate Cancer
Subo Qian1, Shun Zhang1, Yu Wu1
1Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Background:
Protein disulfide isomerase 4 (PDIA4) has been reported to be closely associated with chemoresistance in several types of malignancies. But the pathogenic mechanisms of PDIA4 involved in docetaxel (DTX) resistance in prostate cancer (PCa) are still unknown. Hence, this study was conducted to evaluate the potential effect of PDIA4 on chemoresistance to DTX in PCa cells and to investigate the underlying mechanisms.
Methods:
Two types of DTX-resistant PCa cells, that is, DTX-resistant PC-3 cells (PC-3/DTXR) and C4-2B cells (C4-2B/DTXR) were developed, as well as the parental PC-3 and C4-2B cells were obtained to investigate these issues. Short hairpin RNAs targeting human PDIA4 to knockdown the expression of PDIA4 or PDIA4-expressing adenoviral vectors to overexpress the PDIA4 were transfected into PCa cells to study the underlying mechanisms of PDIA4 involving in PCa DTX resistance.
Results:
Results showed that PDIA4 exhibited a dramatic overexpression in PC-3/DTXR and C4-2B/DTXR cells. Down-regulation of PDIA4 by infecting PC-3/DTXR and C4-2B/DTXR cells with shPDIA4 lentivirus stimulated cell death by prompting apoptosis. Up-regulation of PDIA4 by infecting PC-3 and C4-2B cells with PDIA4-expressing adenovirus showed severer resistance to DTX. In addition, PDIA4 up-regulation induced phosphorylated protein kinase B (Akt) expression, while PDIA4 knockdown significantly inhibited the expression in PCa cells.
Conclusions:
Our study indicates that PDIA4 is a negative regulator of PCa cell apoptosis and plays a critical role in PCa DTX resistance by activating the Akt-signaling pathway. Thereby, it implies that targeting PDIA4 could be a potential adjuvant therapeutic approach against DTX resistance in PCa.
Insights
Protein disulfide isomerase 4 (PDIA4) promotes docetaxel resistance in prostate cancer by activating Akt signaling. Targeting PDIA4 may overcome this resistance, offering a new therapeutic strategy for prostate cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Protein disulfide isomerase 4 (PDIA4) is linked to chemoresistance in various cancers.
- Mechanisms of PDIA4 in docetaxel (DTX) resistance in prostate cancer (PCa) remain unclear.
Purpose of the Study:
- To investigate the role of PDIA4 in DTX resistance in PCa cells.
- To elucidate the underlying molecular mechanisms of PDIA4-mediated DTX resistance.
Main Methods:
- Developed DTX-resistant PCa cell lines (PC-3/DTXR, C4-2B/DTXR).
- Utilized short hairpin RNAs (shPDIA4) to knockdown PDIA4 expression.
- Employed PDIA4-expressing adenoviral vectors to overexpress PDIA4.
Main Results:
- PDIA4 was significantly overexpressed in DTX-resistant PCa cells.
- PDIA4 knockdown induced apoptosis and increased sensitivity to DTX.
- PDIA4 overexpression enhanced DTX resistance and upregulated phosphorylated Akt (p-Akt).
Conclusions:
- PDIA4 acts as a negative regulator of apoptosis in PCa cells.
- PDIA4 confers DTX resistance by activating the Akt signaling pathway.
- Targeting PDIA4 presents a potential adjuvant therapy for overcoming DTX resistance in PCa.
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