ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21
| Autor: | Janét Pittsenbarger, Brooks L. S. Rademacher, Marie C. Lafortune, Anne Myrthue, Chung Ying Huang, Mark Garzotto, Hao Geng, Tomasz M. Beer, Peter S. Nelson, Christopher T. Harvey, David Z. Qian |
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| Rok vydání: | 2010 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Inhibitor of Differentiation Protein 1 Male Cancer Research Tumor suppressor gene Antineoplastic Agents Docetaxel Biology Article Proto-Oncogene Proteins c-myc Prostate cancer Downregulation and upregulation Cell Line Tumor LNCaP medicine Humans Cytotoxicity Cell Proliferation Dose-Response Relationship Drug Cell growth G1 Phase Cancer Prostatic Neoplasms medicine.disease Chromatin Gene Expression Regulation Neoplastic Oncology Cancer research Taxoids Poly(ADP-ribose) Polymerases medicine.drug |
| Zdroj: | Cancer research. 70(8) |
| ISSN: | 1538-7445 |
| Popis: | To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in high-risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy. Among the molecular signatures associated with chemotherapy, transcripts encoding inhibitor of DNA binding 1 (ID1) were significantly upregulated. The patient biochemical relapse status was monitored in a long-term follow-up. Patients with ID1 upregulation were found to be associated with longer relapse-free survival than patients without ID1 increase. This in vivo clinical association was mechanistically investigated. The chemotherapy-induced ID1 upregulation was recapitulated in the prostate cancer cell line LNCaP. Docetaxel dose-dependently induced ID1 transcription, which was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Stable ID1 overexpression in LNCaP increased cell proliferation, promoted G1 cell cycle progression, and enhanced docetaxel-induced cytotoxicity. These changes were accompanied by a decrease in cellular mitochondria content, an increase in BCL2 phosphorylation at serine 70, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel-induced cytotoxicity by inhibiting cell death. ID1-mediated chemosensitivity enhancement was in part due to ID1 suppression of p21. Overexpression of p21 in LNCaP-ID1–overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These molecular data provide a mechanistic rationale for the observed in vivo clinical association between ID1 upregulation and relapse-free survival. Taken together, it shows that ID1 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis. Cancer Res; 70(8); 3239–48. ©2010 AACR. |
| Databáze: | OpenAIRE |
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