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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Long non-coding RNA PCDRlnc1 confers docetaxel resistance in prostate cancer by promoting autophagy
Jianjun Xie1,2, Xiumei Chen3, Weiwan Wang4
1Department of Urology, The First Affiliated Hospital of Soochow University, China.
Abstract:
Docetaxel resistance seriously affects its clinical application in prostate cancer (PCa). Long noncoding RNAs (lncRNAs) influence the chemosensitivity of various cancers. However, the potential involvement of lncRNAs in docetaxel sensitivity remains largely unknown in PCa. In the present study, we used RNA sequencing to compare the expression profiles of lncRNAs in docetaxel-resistant PCa cells and their parental cells and identified a novel lncRNA, ENSG00000234147, termed as PCa docetaxel resistance-associated lncRNA1 (PCDRlnc1). Our results indicated that PCDRlnc1 is closely associated with docetaxel resistance in PCa, and PCDRlnc1 knockout markedly sensitized the resistant cells to docetaxel in vitro and in vivo. In addition, PCDRlnc1 inhibition markedly suppressed docetaxel-induced autophagy. Conversely, PCDRlnc1 overexpression promoted autophagy. Mechanistically, PCDRlnc1 interacted with UHRF1 (ubiquitin-like with plant homeodomain and ring finger domains 1) and promoted its transcription level in PCa cells, leading to the activation of autophagic Beclin-1 signaling. Together, our data demonstrate that PCDRlnc1 is a novel key regulator of PCa docetaxel resistance, suggesting that it may be used as a potential biomarker of docetaxel resistance and therapeutic target in PCa.
Insights
A novel long noncoding RNA, PCDRlnc1, drives docetaxel resistance in prostate cancer (PCa) by promoting autophagy. Inhibiting PCDRlnc1 sensitizes PCa cells to docetaxel, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Docetaxel resistance is a major challenge in prostate cancer (PCa) treatment.
- Long noncoding RNAs (lncRNAs) are implicated in cancer chemosensitivity, but their role in PCa docetaxel resistance is unclear.
Purpose of the Study:
- To identify novel lncRNAs involved in docetaxel resistance in prostate cancer.
- To investigate the functional role and mechanism of a newly identified lncRNA, PCDRlnc1, in PCa docetaxel resistance.
Main Methods:
- RNA sequencing was employed to compare lncRNA expression profiles in docetaxel-resistant and parental PCa cells.
- In vitro and in vivo experiments assessed the effects of PCDRlnc1 knockout and overexpression on docetaxel sensitivity and autophagy.
- Mechanistic studies explored the interaction between PCDRlnc1, UHRF1, and Beclin-1 signaling.
Main Results:
- A novel lncRNA, PCDRlnc1 (ENSG00000234147), was identified and found to be upregulated in docetaxel-resistant PCa cells.
- PCDRlnc1 knockout sensitized PCa cells to docetaxel both in vitro and in vivo.
- PCDRlnc1 inhibition suppressed docetaxel-induced autophagy, while overexpression promoted it, mediated by interaction with UHRF1 and activation of Beclin-1 signaling.
Conclusions:
- PCDRlnc1 is a key regulator of docetaxel resistance in prostate cancer.
- PCDRlnc1 may serve as a potential biomarker for docetaxel resistance and a therapeutic target in PCa treatment.
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