ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21.

Publication Type:

Journal Article

Source:

Cancer research, Volume 70, Issue 8, p.3239-48 (2010)

Keywords:

2010, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Center-Authored Paper, chromatin, Clinical Research Division, Cyclin-Dependent Kinase Inhibitor p21, Dose-Response Relationship, Drug, G1 Phase, Gene Expression Regulation, Neoplastic, Genomics Core Facility, Human Biology Division, Humans, Inhibitor of Differentiation Protein 1, Male, Poly(ADP-ribose) Polymerases, Prostatic Neoplasms, Proto-Oncogene Proteins c-myc, Shared Resources, Taxoids

Abstract:

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 G(1) 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.